List of phenyltropanes

Phenyltropanes (PTs) are a family of chemical compounds originally derived from structural modification of cocaine. The main feature differentiating phenyltropanes from cocaine is that they lack the ester functionality at the 3-position terminating in the benzene; thus, the phenyl is attached direct to the tropane skeleton (hence the name "phenyl"-tropane) with no further spacer that the cocaine benzoyloxy provided. The original purpose of phenyltropane-related research was to extirpate the cardiotoxicity inherent in the local anesthetic "numbing" capability of cocaine (which stems from the methylated benzoate ester being essential to cocaine's blockage of sodium channels, and which causes topical anesthesia) while retaining stimulant function.^{[lower-alpha 1]}

Phenyltropane compounds present promising avenues of research into therapeutic applications, particularly in regard to addiction treatment. These compounds' uses vary depending on their construction and structure-activity relationship ranging from the treating of cocaine dependency to understanding the dopamine reward system in the human brain to treating Alzheimer's and Parkinson's diseases. (Since 2008 there have been continual additions to the list and enumerations of the plethora of types of chemicals that fall into the category of this substance profile.^[2]) Certain phenyltropanes can even be used as a smoking cessation aid (cf. RTI-29). Many of the compounds were first elucidated in published material by the Research Triangle Institute and are thus named with "RTI" serial-numbers (in this case the long form is either RTI-COC-n, for 'cocaine' "analog", or specifically RTI-4229-n of the subsequent numbers given below in this article)^{[lower-alpha 2]} Similarly, a number of others are named for Sterling-Winthrop pharmaceuticals ("WIN" serial-numbers) and Wake Forest University ("WF" serial-numbers). The following includes many of the phenyltropane class of drugs that have been made and studied.

• 
  3D rendering of troparil; which comprises a privileged scaffold of among the phenyltropane class of compounds.
• 
  Troparil structure: cf. U.S. Patent 5,496,953

• 
  Epibatropane^[3] containing a nitrogen heteroatom in the benzene ring formation.
• 
  Tamagnan:^[4] SSRI, SERT = 17(pM) = 10 times the strength of paroxetine for 5HT.
• 
  RTI-298
• 
  (4′-)para-cis-propenyl-phenyl-methylecgonine. A rare SDRI compound with negligible NET affinity (>2,800.0nM displacement value for NET ligand) that retains significant DAT & SERT (15.0nM & 7.1nM) affinity.
• 
  C2-C3 unsaturated (non-isomeric, neither α nor β orientated) 2-naphthyl-tropane
• 
  1-naphthyl-tropane in its usual (comparably non-standard) boat formation of its tropane ring.

Like cocaine, phenyltropanes are considered a 'typical' or 'classical' (i.e. "cocaine-like") DAT re-uptake pump ligands in that they stabilize an "open-to-out" conformation on the dopamine transporter; despite the extreme similarity to phenyltropanes, benztropine and others are in suchwise not considered "cocaine-like" and are instead considered atypical inhibitors insofar as they stabilize what is considered a more inward-facing (closed-to-out) conformational state.^[5]

Considering the differences between PTs and cocaine: the difference in the length of the benzoyloxy and the phenyl linkage contrasted between cocaine and phenyltropanes makes for a shorter distance between the centroid of the aromatic benzene and the bridge nitrogen of the tropane in the latter PTs. This distance being on a scale of 5.6 Å for phenyltropanes and 7.7 Å for cocaine or analogs with the benzoyloxy intact.^{[lower-alpha 3]} The manner in which this sets phenyltropanes into the binding pocket at MAT is postulated as one possible explanation to account for PTs increased behavioral stimulation profile over cocaine.^{[lower-alpha 4]}

Blank spacings within tables for omitted data use "no data", "?", "-" or "—" interchangeably.

2β-carbmethoxy-3β-(4′-substituted phenyl)tropanes (Template:IC50 values)
monohalogen halide-phenyltropanes (11a—11e) alkyl-, & alkenyl-phenyltropanes (11r—11x) alkynyl-phenyltropanes (11y & 11z)

Structure x100px	Short Name i.e. Trivial IUPAC (non-systematic) Name (Singh's #)	R (para-substitution) of benzene	DA [3H]WIN 35428 IC50 nM (Ki nM)	5HT [3H]paroxetine IC50 nM (Ki nM)	NE [3H]nisoxetine IC50 nM (Ki nM)	selectivity 5-HTT/DAT	selectivity NET/DAT
	cocaine (benzoyloxytropane)	H	102 ± 12 241 ± 18ɑ	1045 ± 89 112 ± 2b	3298 ± 293 160 ± 15c	10.2 0.5d	32.3 0.7e
x100px	(para-hydrogen)phenyltropane WIN 35,065-2 (β-CPT[lower-alpha 5]) Troparil 11a	H	23 ± 5.0 49.8 ± 2.2ɑ	1962 ± 61 173 ± 13b	920 ± 73 37.2 ± 5.2c	85.3 3.5d	40.0 0.7e
x100px	para-fluorophenyltropane WIN 35,428 (β-CFT[lower-alpha 6]) 11b	F	14 (15.7 ± 1.4) 22.9 ± 0.4ɑ	156 (810 ± 59) 100 ± 13b	85 (835 ± 45) 38.6 ± 9.9c	51.6 4.4d	53.2 1.7e
x100px	para-nitrophenyltropane 11k	NO2	10.1 ± 0.10	?	?	?	?
x100px	para-aminophenyltropane RTI-29[6] 11j	NH2	9.8 24.8 ± 1.3g	5110	151	521.4	15.4
x100px	para-chlorophenyltropane RTI-31 11c	Cl	1.12 ± 0.06 3.68 ± 0.09ɑ	44.5 ± 1.3 5.00 ± 0.05b	37 ± 2.1 5.86 ± 0.67c	39.7 1.3d	33.0 1.7e
x100px	para-methylphenyltropane RTI-32 Tolpane 11f	Me	1.71 ± 0.30 7.02 ± 0.30ɑ	240 ± 27 19.38 ± 0.65b	60 ± 0.53e 8.42 ± 1.53c	140 2.8d	35.1 1.2e
x100px	para-bromophenyltropane RTI-51 Bromopane 11d	Br	1.81 (1.69) ± 0.30	10.6 ± 0.24	37.4 ± 5.2	5.8	20.7
x100px	para-iodophenyltropane RTI-55 (β-CIT) Iometopane 11e	I	1.26 ± 0.04 1.96 ± 0.09ɑ	4.21 ± 0.3 1.74 ± 0.23b	36 ± 2.7 7.51 ± 0.82c	3.3 0.9d	28.6 3.8e
x100px	para-hydroxyphenyltropane 11h	OH	12.1 ± 0.86	—	—	—	—
x100px	para-methoxyphenyltropane 11i	OCH3	8.14 ± 1.3	—	—	—	—
x100px	para-azidophenyltropane 11l	N3	2.12 ± 0.13	—	—	—	—
x100px	para-trifluoromethylphenyltropane 11m	CF3	13.1 ± 2.2	—	—	—	—
x100px	para-acetylaminophenyltropane 11n	NHCOCH3	64.2 ± 2.6	—	—	—	—
x100px	para-propionylaminophenyltropane 11o	NHCOC2H5	121 ± 2.7	—	—	—	—
x100px	para-ethoxycarbonylaminophenyltropane 11p	NHCO2C3H5	316 ± 48	—	—	—	—
x100px	para-trimethylstannylphenyltropane 11q	Sn(CH3)3	144 ± 37	—	—	—	—
x100px	para-ethylphenyltropane RTI-83 11g	Et	55 ± 2.1	28.4 ± 3.8 (2.58 ± 3.5)	4030 (3910) ± 381 (2360 ± 230)	0.5	73.3
x100px	para-n-propylphenyltropane RTI-282i 11r	n-C3H7	68.5 ± 7.1	70.4 ± 4.1	3920 ± 130	1.0	57.2
x100px	para-isopropylphenyltropane 11s	CH(CH3)2	597 ± 52	191 ± 9.5	75000 ± 5820	0.3	126
x100px	para-vinylphenyltropane RTI-359 11t	CH-CH2	1.24 ± 0.2	9.5 ± 0.8	78 ± 4.1	7.7	62.9
x100px	para-methylethenylphenyltropane RTI-283j 11u	C(=CH2)CH3	14.4 ± 0.3	3.13 ± 0.16	1330 ± 333	0.2	92.4
x100px	para-trans-propenylphenyltropane RTI-296i 11v	trans-CH=CHCH3	5.29 ± 0.53	11.4 ± 0.28	1590 ± 93	2.1	300
x100px	para-allylphenyltropane 11x	CH2CH=CH2	32.8 ± 3.1	28.4 ± 2.4	2480 ± 229	0.9	75.6
x100px	para-ethynylphenyltropane RTI-360 11y	C≡CH	1.2 ± 0.1	4.4 ± 0.4	83.2 ± 2.8	3.7	69.3
x100px	para-propynylphenyltropane RTI-281i 11z	C≡CCH3	2.37 ± 0.2	15.7 ± 1.5	820 ± 46	6.6	346
x100px	para-cis-propenylphenyltropane RTI-304 11w	cis-CH=CHCH3	15 ± 1.2	7.1 ± 0.71	2,800k ± 300	0.5	186.6k
x140px	para-(Z)-phenylethenylphenyltropane	cis-CH=CHPh	11.7 ± 1.12	—	—	—	—
x100px	para-benzylphenyltropane	-CH2-Ph	526 ± 65	7,240 ± 390 (658 ± 35)	6670 ± 377 (606 ± 277)	13.7	12.6
x100px	para-phenylethenylphenyltropane	CH2 ║ -C-Ph	474 ± 133	2,710 ± 800 (246 ± 73)	7,060 ± 1,760 (4,260 ± 1,060)	5.7	14.8
x100px	para-phenylethylphenyltropanel	-(CH2)2-Ph	5.14 ± 0.63	234 ± 26 (21.3 ± 2.4)	10.8 ± 0.3 (6.50 ± 0.20)	45.5	2.1
x100px	para-(E)-phenylethenylphenyltropanel RTI-436	trans–CH=CHPh	3.09 ± 0.75	335 ± 150 (30.5 ± 13.6)	1960 ± 383 (1180 ± 231)	108.4	634.3
x120px	para-phenylpropylphenyltropanel	-(CH2)3-Ph	351 ± 52	1,243 ± 381 (113 ± 35)	14,200 ± 1,800 (8,500 ± 1,100)	3.5	40.4
x120px	para-phenylpropenylphenyltropanel	-CH=CH-CH2-Ph	15.8 ± 1.31	781 ± 258 (71 ± 24)	1,250 ± 100 (759 ± 60)	49.4	79.1
x100px	para-phenylbutylphenyltropanel	-(CH2)4-Ph	228 ± 21	4,824 ± 170 (439 ± 16)	2,310 ± 293 (1,390 ± 177)	21.1	10.1
x100px	para-phenylethynylphenyltropanel RTI-298[7]	–≡–Ph	3.7 ± 0.16	46.8 ± 5.8 (4.3 ± 0.53)	347 ± 25 (209 ± 15)	12.6	93.7
x100px	para-phenylpropynylphenyltropanel[8]	–C≡C-CH2Ph	1.82 ± 0.42	13.1 ± 1.7 (1.19 ± 0.42)	27.4 ± 2.6 (16.5 ± 1.6)	7.1	15
x100px	para-phenylbutynylphenyltropanel RTI-430	–C≡C(CH2)2Ph	6.28 ± 1.25	2180 ± 345 (198 ± 31)	1470 ± 109 (885 ± 66)	347.1	234
x100px	para-phenylpentynylphenyltropanel	–C≡C-(CH2)3-Ph	300 ± 37	1,340 ± 232 (122 ± 21)	4,450 ± 637 (2,680 ± 384)	4.46	14.8
x100px	para-trimethylsilylethynylphenyltropane[3]	—	—	—	—	—	—
x100px	para-hydroxypropynylphenyltropane[3]	—	—	—	—	—	—
x100px	para-hydroxyhexynylphenyltropanel	–C≡C-(CH2)4OH	57 ± 4	828 ± 29 (75 ± 2.6)	9,500 ± 812 (5,720 ± 489)	14.5	166.6
x100px	para-(thiophen-3-yl)phenyltropane Tamagnan[4]	p-thiophene	12	0.017	189	0.001416	15.7
x100px	para-biphenyltropane 11aa	Ph	10.3 ± 2.6f 29.4 ± 3.8ɑ 15.6 ± 0.6	95.8 ± 36 (8.7 ± 3.3)	1,480 ± 269 (892 ± 162)	6.1	94.8
x110px	3β-2-naphthyltropane RTI-318 11bb	3β-2-naphthyl	0.51 ± 0.03 3.32 ± 0.08f 3.53 ± 0.09ɑ	0.80 ± 0.06 (0.07 ± 0.1)	21.1 ± 1.0 (12.7 ± 0.60)	1.5	41.3
x100px	para-bimethoxyphenyltropane 15	OCH2OCH3h	—	—	—	—	—

ɑ[3H]DA uptake displacement Ki value. b[3H]5-HT uptake displacement Ki value. c[3H]NE uptake displacement Ki value.

d[3H]5-HT uptake to [3H]DA uptake ratio. e[3H]NE uptake to [3H]DA uptake ratio. fIC50 for displacement of [3H]cocaine. gValues from alternate data-set differing from that used in rest of table. hOriginal source (Scheme 4, page 931, 7th of article)[1] name given for compound (bottom of first ¶) is at variance with formula in scheme on same page: i.e. "methoxymethyl" versus "methoxymethoxy"

iProtonated as the (-)—tartrate salt (isomer) jProtonated as the tartrate salt kWas cited by S. Singh as 28,000nM for SERT or a DAT/SERT ratio of 1,867. However, in Singh's paper he cited J. Med. Chem. 1996, 39, 4030, Table 1[9] which shows a ten times lower value, which is consistent with numerous RTI patents published showing the ten-× lower value. lWhereas many bulky additions to the arene unit of phenyltropanes hinder and impair affinity, it has been observed that the para-substituted rigid triple bond analogs terminating in a second phenyl (off of the initial C3 position phenyl) have a high-binding affinity, putatively attesting to the existence of another binding domain that extends beyond the usual ending point where the benzene accords to the acceptor somewhere along the length of range inhabited by the DAT, corresponding to a 180° extension outward from the para area of the aryl of these types of ligands.[8]

Tamagnan (thiophene) analogues of para-phenyltropanes.^[4]

Compound structure	Alphanumeric code (name)	para-substitution	N8	SERT	DAT	NET	Selectivity SERT versus DAT	Selectivity SERT versus NET
	1 (cocaine)	(—)-Cocaine	CH3	1050	89	3320	0.08	3.2
	2 (β-CIT), (Iometopane)	Iodo	CH3	0.46 ± 0.06	0.96 ± 0.15	2.80 ± 0.40	2.1	6.1
	(R,S-Citalopram)	—	—	1.60	16,540	6,190	10,338	3,869
x100px	4a	2-Thiophene	CH3	0.15 ± 0.015	52 ± 12.8	158 ± 12	346	1,053
x100px	4b (Tamagnan)	3-Thiophene	CH3	0.017 ± 0.004	12.1 ± 3	189 ± 82	710	11,118
x100px	4c	2-(5-Br)-Thiophene	CH3	0.38 ± 0.008	6.43 ± 0.9	324 ± 19	17	853
x100px	4d	2-(5-Cl)-Thiophene	CH3	0.64 ± 0.04	4.42 ± 1.64	311 ± 25	6.9	486
x100px	4e	2-(5-I)-Thiophene	CH3	4.56 ± 0.84	22.1 ± 3.2	1,137 ± 123	4.9	249
x100px	4f	2-(5-NH2)-Thiophene	CH3	64.7 ± 3.7	>10,000	>30,000	>155	>464
x100px	4g	2-(4,5-NO2)-Thiophene	CH3	5,000	>30,000	>10,000	>6.0	>2.0
x100px	4h	3-(4-Br)-Thiophene	CH3	4.02 ± 0.34	183 ± 69	>10,000	46	>2,488
x100px	5a	2-Thiophene	H	0.11 ± 0.006	12.2 ± 0.9	75.3 ± 9.6	111	685
x100px	5b	3-Thiophene	H	0.23 ± 0.02	6.4 ± 0.27	39 ± 0.8	28	170

• 
• 
• 
• 

Compound (+ S. Singh's name)	X (4′-para)	Y (3′-meta)	2 Position	config	8	DA	5-HT	NE
RTI-318 11bb	β-naphthyl		CO2Me	β,β	NMe	0.5	0.81	20
Dichloropane (RTI-111ɑ)[10] 17c	Cl	Cl	CO2Me	β,β	NMe	0.79	3.13	18.0
RTI-88 [recheck] 17e	NH2	I	CO2Me	β,β	NMe	1.35	1329c	320c
RTI-97 17d	NH2	Br	CO2Me	β,β	NMe	3.91	181	282
RTI-112b 17b	Cl	Me	CO2Me	β,β	NMe	0.82	10.5	36.2
RTI-96 17a	F	Me	CO2Me	β,β	NMe	2.95	76	520
RTI-295	Et	I	CO2Me	β,β	NMe	21.3	2.96	1349
RTI-353 (EINT)	Et	I	CO2Me	β,β	NH	331	0.69	148
RTI-279	Me	I	CO2Me	β,β	NH	5.98	1.06	74.3
RTI-280	Me	I	CO2Me	β,β	NMe	3.12	6.81	484
Meltzer[11]	catechol		CO2Me	β,β	NMe	>100	?	?
Meltzer[11]	OAc	OAc	CO2Me	β,β	NMe	?	?	?

• ^ɑas ·HCl (salt)
• ^bas ·HCl·2 H₂O (salt)
• ^cSingh gives the reverse value with respect to i.e. 1,329 for NET & 320 for 5-HT

Para-meta-substituted 2β-carbomethoxy-3α-(4′-substituted phenyl)tropanes^[1]

Compound 150px	Short Name (S. Singh)	R2	R1	DA	5HT	NE	Selectivity 5-HTT/DAT	Selectivity NET/DAT
150px	meta-fluorophenyltropane 16a	F	H	23 ± 7.8	-	-	-	-
150px	meta-chlorophenyltropane 16b	Cl	H	10.6 ± 1.8	-	-	-	-
150px	meta-bromophenyltropane 16c	Br	H	7.93 ± 0.08ɑ	-	-	-	-
150px	meta-iodophenyltropane 16d	I	H	26.1 ± 1.7	-	-	-	-
160px	meta-tributylstannylphenyltropane 16e	SnBu3	H	1100 ± 170	-	-	-	-
160px	meta-ethynylphenyltropane[3]	C≡CH	H	-	-	-	-	-
150px	meta-methyl-para-fluorophenyltropane RTI-96 17a	CH3	F	2.95 ± 0.58	-	-	-	-
150px	meta-methyl-para-chlorophenyltropane RTI-112c 17b	CH3	Cl	0.81 ± 0.05	10.5 ± 0.05	36.2 ± 1.0	13.0	44.7
150px	meta-para-dichlorophenyltropane RTI-111b[10] Dichloropane 17c	Cl	Cl	0.79 ± 0.08b	3.13 ± 0.36b	18.0 ± 0.8 17.96 ± 0.85'b'd	4.0b	22.8b
160px	meta-bromo-para-aminophenyltropane RTI-97 17d	Br	NH2	3.91 ± 0.59	181	282	46.2	72.1
160px	meta-iodo-para-aminophenyltropane RTI-88 17e	I	NH2	1.35 ± 0.11	120 ± 4	1329 ± 124	88.9	984
160px	meta-iodo-para-azidophenyltropane 17f	I	N3	4.93 ± 0.32	-	-	-	-

• ^ɑIC₅₀ determined in Cynomolgous monkey caudate-putamen
• ^bas ·HCl (salt)
• ^cas ·HCl·2 H₂O (salt)
• ^dNE_N

3β-(4-alkylthio, -methylsulfinyl, and -methylsulfonylphenyl)tropanes^[12]

Structure 150px	Compound	R	X	n	Inhibition of [3H]WIN 35,428 @ DAT IC50 (nM)	Inhibition of [3H]Paroxetine @ 5-HTT Ki (nM)	Inhibition of [3H]Nisoxetine @ NET Ki (nM)	NET/DAT (uptake ratio)	NET/5-HTT (uptake ratio)
	Cocaine	Des-thio/sulfinyl/sulfonyl H	H	Desmethyl 0	89.1	95	1990	22	21
	para-methoxyphenyltropane Singh: 11i	Des-thio/sulfinyl/sulfonyl OCH3	H	0	6.5 ± 1.3	4.3 ± 0.5	1110 ± 64	171	258
190px	7a	CH3	H	0	9 ± 3	0.7 ± 0.2	220 ± 10	24	314
200px	7b	C2H5	H	0	232 ± 34	4.5 ± 0.5	1170 ± 300	5	260
200px	7c	CH(CH3)2	H	0	16 ± 2	23 ± 2	129 ± 2	8	7
200px	7d	CF3	H	0	200 ± 70	8 ± 2	1900 ± 300	10	238
180px	7e	CH3	Br	0	10.1 ± 1	0.6 ± 0.2	121 ± 12	12	202
180px	7f	CH3	Br	1	76 ± 18	3.2 ± 0.4	690 ± 80	9	216
180px	7g	CH3	H	1	91 ± 16	4.3 ± 0.6	515 ± 60	6	120
180px	7h	CH3	H	2	>10,000	208 ± 45	>10,000	1	48

Ortho-para-substituted (2′,4′-disubstituted phenyltropanes)

Compound structure x130px	Trivial IUPAC (non-systematic) Name	R2 ortho	R1 para	DA	5HT	NE	Selectivity 5-HTT/DAT	Selectivity NET/DAT
185px	ortho,para-dinitrophenyltropane[13]	NO2	NO2	-	-	-	-	-

Para-meta(3′)-meta(5′)-(di-meta)-substituted 2β-carbomethoxy-(3′,4′,5′-substituted phenyl)tropanes^[14]
Para-methoxy/(ethoxy)-meta-substituted phenyltropanes

Structure 210px	Script error: No such module "Vertical header".	Script error: No such module "Vertical header".	Script error: No such module "Vertical header".	Script error: No such module "Vertical header".	DAT IC50 [3 H](compound #)12	5-HTT Ki [3 H]Paroxetine	NET Ki [3 H]Nisoxetine	Selectivity NET/DAT Ratio Ki/IC50	Selectivity NET/5-HTT Ratio Ki/Ki
	Cocaine	-	-	-	89.1	95	1990	22	21
	6 RTI-112	-	-	-	0.82 ± 0.05	0.95 ± 0.04	21.8 ± 0.6	27	23
	7a 11i	H	H	CH3	6.5 ± 1.3	4.3 ± 0.5	1110 ± 64	171	258
	7b	H	H	C2H5	92 ± 8	1.7 ± 0.4	1690 ± 50	18	994
	7c	F	H	CH3	16 ± 1	4.8 ± 0.5	270 ± 50	17	56
	7d	Br	H	CH3	47 ± 15	3.1 ± 0.1	160 ± 20	3	52
	7f	Br	Br	CH3	92 ± 22	2.9 ± 0.1	4100 ± 400ɑ	45	1413
	7e	I	H	CH3	170 ± 60	3.5 ± 0.4	180 ± 20	1	51
	7g	I	I	CH3	1300 ± 200	7.5 ± 0.8	180 ± 20	4	667

^ɑN=2

Ortho-para(4′)-meta(5′)-trisubstituted 2β-carbomethoxy-(2′,4′,5′-substituted phenyl)tropanes^[3]

Structure	Short Name	Script error: No such module "Vertical header".	Script error: No such module "Vertical header".	Script error: No such module "Vertical header".	Script error: No such module "Vertical header".	Script error: No such module "Vertical header".	Script error: No such module "Vertical header".	Selectivity NET/DAT Ratio	Selectivity NET/5-HTT Ratio
x130px	para-ethyl-ortho, meta-diiodophenyltropane[3]	iodo	ethyl	iodo	—	—	—	—	—

Template:Sort-under

Para-OCH₃-(3β-(4-Methoxyphenyl)tropane-2β-carboxylic acid ester analogues^[15]

Structure 200px	Script error: No such module "Vertical header".	CO2R (2β-substituted) (compound 9 is 2β=R)	DAT IC50 [3 H](compound #)12	5-HTT Ki [3 H]Paroxetine	NET Ki [3 H]Nisoxetine	Selectivity NET/DAT Ratio Ki/IC50	Selectivity NET/5-HTT Ratio Ki/Ki
	7a 11i	CH3	6.5 ± 1.3	4.3 ± 0.5	1110 ± 64	171	258
	8a	(CH3)2CH	14 ± 3	135 ± 35	2010 ± 200	144	15
	8b	cyclopropane	6.0 ± 2	29 ± 3	1230 ± 140	205	42
	8c	cyclobutane	13 ± 3	100 ± 8	>3000	231	30
	8d	O2N...1,4-xylene...(CH2)2	42 ± 8	2.9 ± 0.2	330 ± 20	8	114
	8e	H2N...1,4-xylene...(CH2)2	7.0 ± 2	8.3 ± 0.4	2200 ± 300ɑ	314	265
	8f	CH3CONH...1,4-xylene...(CH2)2	6.0 ± 1	5.5 ± 0.5	1460 ± 30	243	265
	8g	H2N...2-bromo-1,4-dimethylbenzene...(CH2)2	3.3 ± 1.4	4.1 ± 0.6	1850 ± 90	561	451
	8h	H2N...1,3-dibromo-2,5-dimethylbenzene...(CH2)2	15 ± 6	2.0 ± 0.4	2710 ± 250ɑ	181	1360
	8i	H2N...2-iodo-1,4-dimethylbenzene...(CH2)2	2.5 ± 0.7	3.5 ± 1	2040 ± 300ɑ	816	583
	8j	H2N...1,3-diiodo-2,5-dimethylbenzene...(CH2)2	102 ± 15	1.0 ± 0.1	2600 ± 200ɑ	25	2600
	9	3-(4-methylphenyl)-1,2-oxazole	18 ± 6	860 ± 170	>3000	167	3

^ɑN=2

Multi-substituted structures of 2β-ester-3β-phenyltropanes^[1]

Compound 150px	Short Name (S. Singh)	R	X	IC50 (nM) DAT [3H]WIN 35428	IC50 (nM) 5-HTT [3H]paroxetine	IC50 (nM) NET [3H]nisoxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT
x100px	23a	CH(CH3)2	H	85.1 ± 2.5	23121 ± 3976	32047 ± 1491	272	376
x120px	23b	C6H5	H	76.7 ± 3.6	106149 ± 7256	19262 ± 593	1384	251
x100px	24a	CH(CH3)2	Cl	1.4 ± 0.13 6.04 ± 0.31ɑ	1400 ± 7 128 ± 15b	778 ± 21 250 ± 0.9c	1000 21.2d	556 41.4e
x100px	24b	cyclopropyl	Cl	0.96 ± 0.10	168 ± 1.8	235 ± 8.39	175	245
x120px	24c	C6H5	Cl	1.99 ± 0.05 5.25 ± 0.76ɑ	2340 ± 27 390 ± 34b	2960 ± 220 242 ± 30c	1176 74.3d	1.3 41.6e
x150px	24d	C6H4-4-I	Cl	32.6 ± 3.9	1227 ± 176	967.6 ± 26.3	37.6	29.7
x120px	24e	C6H4-3-CH3	Cl	9.37 ± 0.52	2153 ± 143	2744 ± 140	230	293
x140px	24f	C6H4-4-CH3	Cl	27.4 ± 1.5	1203 ± 42	1277 ± 118	43.9	46.6
x120px	24g	C6H4-2-CH3	Cl	3.91 ± 0.23	3772 ± 384	4783 ± 387	965	1223
x140px	24h	C6H4-4-Cl	Cl	55 ± 2.3	16914 ± 1056	4883 ± 288	307	88.8
x150px	24i	C6H4-4-OCH3	Cl	71 ± 5.6	19689 ± 1843	1522 ± 94	277	21.4
x150px	24j	(CH2)2C6H4-4-NO2	Cl	2.71 ± 0.13	-	-	-	-
x150px	24k	(CH)2C6H4-4-NH2	Cl	2.16 ± 0.25	-	-	-	-
x150px	24l	(CH2)2C6H3-3-I-4-NH2	Cl	2.51 ± 0.25	-	-	-	-
x150px	24m	(CH2)2C6H3-3-I-4-N3	Cl	14.5 ± 0.94	-	-	-	-
x150px	24n	(CH2)2C6H4-4-N3	Cl	6.17 ± 0.57	-	-	-	-
x150px	24o	(CH2)2C6H4-4-NCS	Cl	5.3 ± 0.6	-	-	-	-
x170px	24p	(CH2)2C6H4-4-NHCOCH2Br	Cl	1.73 ± 0.06	-	-	-	-
x100px	25a	CH(CH3)2	I	0.43 ± 0.05 2.79 ± 0.13ɑ	66.8 ± 6.53 12.5 ± 1.0b	285 ± 7.6 41.2 ± 3.0c	155 4.5d	663 14.8e
x100px	25b	cyclopropyl	I	0.61 ± 0.08	15.5 ± 0.72	102 ± 11	25.4	167
x120px	25c	C6H5	I	1.51 ± 0.34 6.85 ± 0.93ɑ	184 ± 22 51.6 ± 6.2b	3791 ± 149 32.7 ± 4.4c	122 7.5d	2510 4.8e
x100px	26a	CH(CH3)2	CH3	6.45 ± 0.85 15.3 ± 2.08ɑ	6090 ± 488 917 ± 54b	1926 ± 38 73.4 ± 11.6c	944 59.9d	299 4.8e
x120px	26b	CH(C2H5)2	CH3	19.1 ± 1	4499 ± 557	3444 ± 44	235	180
x100px	26c	cyclopropyl	CH3	17.8 ± 0.76	485 ± 21	2628 ± 252	27.2	148
x110px	26d	cyclobutyl	CH3	3.74 ± 0.52	2019 ± 133	4738 ± 322	540	1267
x120px	26e	cyclopentyl	CH3	1.68 ± 0.14	1066 ± 109	644 ± 28	634	383
x120px	26f	C6H5	CH3	3.27 ± 0.06 9.13 ± 0.79ɑ	24500 ± 1526 1537 ± 101b	5830 ± 370 277 ± 23c	7492 168d	1783 30.3e
x120px	26g	C6H4-3-CH3	CH3	8.19 ± 0.90	5237 ± 453	2136 ± 208	639	261
x140px	26h	C6H4-4-CH3	CH3	81.2 ± 16	15954 ± 614	4096 ± 121	196	50.4
x120px	26i	C6H4-2-CH3	CH3	23.2 ± 0.97	11040 ± 504	25695 ± 1394	476	1107
x150px	26j	C6H4-4-Cl	CH3	117 ± 7.9	42761 ± 2399	9519 ± 864	365	81.3
x150px	26k	C6H4-4-OCH3	CH3	95.6 ± 8.8	82316 ± 7852	3151 ± 282	861	33.0

• ^ɑKi value for displacement of [³H]DA uptake.
• ^bKi value for displacement of [³H]5-HT uptake.
• ^cKi value for displacement of [³H]NE uptake.
• ^d[³H]5-HT uptake to [³H]DA uptake ratio.
• ^e[³H]NE uptake to [³H]DA uptake ratio.

Compound	X	2 Position	config	8	DA	5-HT	NE
RTI-122	I	-CO2Ph	β,β	NMe	1.50	184	3,791
RTI-113	Cl	-CO2Ph	β,β	NMe	1.98	2,336	2,955
RTI-277	NO2	-CO2Ph	β,β	NMe	5.94	2,910	5,695
RTI-120 [recheck]	Me	-CO2Ph	β,β	NMe	3.26	24,471	5,833
RTI-116	Cl	-CO2(p-C6H4I)	β,β	NMe	33	1,227	968
RTI-203	Cl	CO2(m-C6H4Me)	β,β	NMe	9.37	2153	2744
RTI-204	Cl	-CO2(o-C6H4Me)	β,β	NMe	3.91	3,772	4,783
RTI-205	Me	-CO2(m-C6H4Me)	β,β	NMe	8.19	5,237	2,137
RTI-206	Cl	-CO2(p-C6H4Me)	β,β	NMe	27.4	1,203	1,278

2-Phenyl-3-phenyltropane binding affinities and inhibition of DA & 5-HT Uptake^[1]

Compound Structure	Script error: No such module "Vertical header".	Script error: No such module "Vertical header".	X (para)	DAT [3H]WIN 35428 IC50 (nM)	DAT [3H]Mazindol Ki (nM)	5-HTT [3H]Paroxetine IC50 (nM)	[3H]DA uptake Ki (nM)	[3H]5-HT uptake Ki (nM)	Selectivity [3H]5-HT/[3H]DA
	Cocaine	(2β,3β)	(H)	89 ± 4.8	281	1050 ± 89	423	155	0.4
x105px	67a	2β,3β	H	12.6 ± 1.8	14.9	21000 ± 3320	28.9	1100	38.1
x155px	67b	2β,3α	H	-	13.8	-	11.7	753	64.3
x135px	67c	2α,3α	H	690 ± 37	-	41300 ± 5300	-	-	-
x170px	68	2β,3α	F	-	6.00	-	4.58	122	26.6
x100px	69a	2β,3β	CH3	1.96 ± 0.08	2.58	11000 ± 83	2.87	73.8	25.7
x170px	69b	2β,3α	CH3	-	2.87	-	4.16	287	69.0
x145px	69c	2α,3α	CH3	429 ± 59	-	15800 ± 3740	-	-	-

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Code	X	2 Position	config	8	DA	5-HT	NE
RTI-77	Cl	CH2C2(3-iodo-p-anilino)	β,β	NMe	2.51	—	2247
RTI-121 IPCIT	I	-CO2Pri	β,β	NMe	0.43	66.8	285
RTI-153	I	-CO2Pri	β,β	NH	1.06	3.59	132
RTI-191	I	-CO2Prcyc	β,β	NMe	0.61	15.5	102
RTI-114	Cl	-CO2Pri	β,β	NMe	1.40	1,404	778
RTI-278	NO2	-CO2Pri	β,β	NMe	8.14	2,147	4,095
RTI-190	Cl	-CO2Prcyc	β,β	NMe	0.96	168	235
RTI-193	Me	-CO2Prcyc	β,β	NMe	1.68	1,066	644
RTI-117	Me	-CO2Pri	β,β	NMe	6.45	6,090	1,926
RTI-150	Me	-CO2Bucyc	β,β	NMe	3.74	2,020	4,738
RTI-127	Me	-CO2C(H)Et2	β,β	NMe	19	4500	3444
RTI-338	ethyl	-CO2C2Ph	β,β	NMe	1104	7.41	3366

Use of a cyclopropyl ester appears to enable better MAT retention than does the choice of isopropyl ester.

Use of a ^cycBu resulted in greater DAT selectivity than did the ^cycPr homologue.

2β-Alkyl Ester Phenyltropanes^[1]

Structure	Short Name (S. Singh)	2β=R	Ki (nM) DAT [3H]WIN 35428	IC50 (nM) [3H]DA uptake	Selectivity uptake/binding
x110px	59a	CH=CHCO2CH3	22 ± 2	123 ± 65	5.6
x110px	59b	CH2CH2CO2CH3	23 ± 2	166 ± 68	7.2
x120px	59c	(CH2)2CH=CHCO2CH3	20 ± 2	203 ± 77	10.1
x120px	59d	(CH22)4CO2CH3	30 ± 2	130 ± 7	4.3
x90px	59e	CH=CHCH2OH	26 ± 3	159 ± 43	6.1
x90px	59f	CH2CH2CH2OH	11 ± 1	64 ± 32	5.8
x110px	59g	CH2CH2COC6H5	28 ± 2	47 ± 15	1.7

2-Alkyl Ether Phenyltropanes^[1]

Molecular Structure	Short Name (S. Singh)	Script error: No such module "Vertical header".	DAT [3H]WIN 35428 IC50 (nM)	5-HTT [3H]Paroxetine IC50 (nM)	NET [3H]Nisoxetine IC50 (nM)	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	Paroxetine		623 ± 25	0.28 ± 0.02	535 ± 15	0.0004	0.8
x130px	R-60a	2β,3β	308 ± 20	294 ± 18	5300 ± 450	0.9	17.2
x115px	R-60b	2α,3β	172 ± 8.8	52.9 ± 3.6	26600 ± 1200	0.3	155
x195px	R-60c	2β,3α	3.01 ± 0.2	42.2 ± 16	123 ± 9.5	14.1	40.9
x130px	S-60d	2β,3β	1050 ± 45	88.1 ± 2.8	27600 ± 1100	0.08	26.3
x115px	S-60e	2α,3β	1500 ± 74	447 ± 47	2916 ± 1950	0.3	1.9
x195px	S-60f	2β,3α	298 ± 17	178 ± 13	12400 ± 720	0.6	41.6

U.S. Patent 5,736,123

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Template:Sort-under

Structure x100px	Script error: No such module "Vertical header".	X	2 Position	Script error: No such module "Vertical header".	8	DA [3H]WIN 35428 (IC50 nM)	NE [3H]nisoxetine	5-HT [3H]paroxetine (IC50 nM)	Selectivity 5-HTT/DAT	Selectivity NET/DAT
x100px	RTI-106 27b	Cl	CON(H)Me	β,β	NMe	12.4 ± 1.17	1584 ± 62	1313 ± 46	106	128
x100px	RTI-118 27a	Cl	CONH2	β,β	NMe	11.5 ± 1.6	4270 ± 359	1621 ± 110	141	371
x100px	RTI-222 29d	Me	morpholinyl	β,β	NMe	11.7 ± 0.87	23601 ± 1156	>100K	>8547	2017
x100px	RTI-129 27e	Cl	CONMe2	β,β	NMe	1.38 ± 0.1	942 ± 48	1079 ± 102	792	683
x100px	RTI-146 27d	Cl	CONHCH2OH	β,β	NMe	2.05 ± 0.23	144 ± 3	97.8 ± 10	47.7	70.2
x100px	RTI-147 27i	Cl	CON(CH2)4	β,β	NMe	1.38 ± 0.03	3,950 ± 72	12400 ± 1207	8985	2862
x100px	RTI-156	Cl	CON(CH2)5	β,β	NMe	6.61	5832	3468
x100px	RTI-170	Cl	CON(H)CH2C≡CH	β,β	NMe	16.5	1839	4827
x100px	RTI-172	Cl	CON(H)NH2	β,β	NMe	44.1	3914	3815
x130px	RTI-174	Cl	CONHCOMe	β,β	NMe	158	>43K	>125K
x160px	RTI-182	Cl	CONHCH2COPh	β,β	NMe	7.79	1722	827
x110px	RTI-183✲ 27 g	Cl	CON(OMe)Me	β,β	NMe	0.85 ± 0.06	549 ± 18.5	724 ± 94	852	646
x110px	RTI-186 29c	Me	CON(OMe)Me	β,β	NMe	2.55 ± 0.43	422 ± 26	3402 ± 353	1334	165
x100px	RTI-198 27h	Cl	CON(CH2)3	β,β	NMe	6.57 ± 0.67	990 ± 4.8	814 ± 57	124	151
x100px	RTI-196 27c	Cl	CONHOMe	β,β	NMe	10.7 ± 1.25	9907 ± 632	43700 ± 1960	4084	926
x160px	RTI-201	Cl	CONHNHCOPh	β,β	NMe	91.8	>20K	>48K
x110px	RTI-208 27j	Cl	CONO(CH2)3	β,β	NMe	1.47 ± 0.13	1083 ± 76	2470 ± 56	1680	737
x110px	RTI-214 27l	Cl	CON(-CH2CH2-)2O	β,β	NMe	2.90 ± 0.3	8545 ± 206	88769 ± 1855	30610	2946
x110px	RTI-215 27f	Cl	CONEt2	β,β	NMe	5.48 ± 0.19	5532 ± 299	9433 ± 770	1721	1009
x150px	RTI-217	Cl	CONH(m-C6H4OH)	β,β	NMe	4.78	>30K	>16K
x100px	RTI-218✲	Cl	CON(Me)OMe	β,β	NMe	1.19	520	1911
x150px	RTI-226 27 m	Cl	CONMePh	β,β	NMe	45.5 ± 3	2202 ± 495	23610 ± 2128	519	48.4
x100px	RTI-227	I	CONO(CH2)3	β,β	NMe	0.75	446	230
x100px	RTI-229[16] 28a	I	CON(CH2)4	β,β	NMe	0.37 ± 0.04	991 ± 21	1728 ± 39	4670	2678
x100px	27k					6.95 ± 1.21	1752 ± 202	3470 ± 226	499	252
x100px	28b					1.08 ± 0.15	103 ± 6.2	73.9 ± 8.1	68.4	95.4
x110px	28c					0.75 ± 0.02	357 ± 42	130 ± 15.8	173	476
x100px	29a					41.8 ± 2.45	4398 ± 271	6371 ± 374	152	105
x110px	29b					24.7 ± 1.93	6222 ± 729	33928 ± 2192	1374	252

✲RTI-183 and RTI-218 suggest possible copy-error, seeing as "CON(OMe)Me" & "CON(Me)OMe" difference between methyl & methoxy render as the same.

2β-Carboxamide-3β-Phenyltropanes^[1]

Compound	Short Name (S. Singh)	R	X	IC50 (nM) DAT [3H]WIN 35428	IC50 (nM) 5-HTT [3H]Paroxetine	IC50 (nM) NET [3H]Nisoxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT
x100px
	29a	NH2	CH3	41.8 ± 2.45	6371 ± 374	4398 ± 271	152	105
	29b	N(CH2CH3)2	CH3	24.7 ± 1.93	33928 ± 2192	6222 ± 729	1374	252
	29c RTI-186	N(OCH3)CH3	CH3	2.55 ± 0.43	3402 ± 353	422 ± 26	1334	165
	29d RTI-222	4-morpholine	CH3	11.7 ± 0.87	>100000	23601 ± 1156	>8547	2017

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Dimers of phenyltropanes, connected in their dual form using the C2 locant as altered toward a carboxamide structural configuring (in contrast and away from the usual inherent ecgonine carbmethoxy), as per Frank Ivy Carroll's patent inclusive of such chemical compounds, possibly so patented due to being actively delayed pro-drugs in vivo.^[3]

These heterocycles are sometimes referred to as the "bioisosteric equivalent" of the simpler esters from which they are derived. A potential disadvantage of leaving the ββ-ester unreacted is that in addition to being hydrolyzable, it can also epimerize^[17] to the energetically more favorable trans configuration. This can happen to cocaine also.

Several of the oxadiazoles contain the same number and types of heteroatoms, while their respective binding potencies display 8×-15× difference. A finding that would not be accounted for by their affinity originating from hydrogen bonding.

To explore the possibility of electrostatic interactions, the use of molecular electrostatic potentials (MEP) were employed with model compound 34 (replacing the phenyltropane moiety with a methyl group). Focusing on the vicinity of the atoms @ positions A—C, the minima of electrostatic potential near atom position A (ΔV_min(A)), calculated with semi-empirical (AM1) quantum mechanics computations (superimposing the heterocyclic and phenyl rings to ascertain the least in the way of steric and conformational discrepancies) found a correlation between affinity @ DAT and ΔV_min(A): wherein the values for the latter for 32c = 0, 32g = -4, 32h = -50 & 32i = -63 kcal/mol.

In contrast to this trend, it is understood that an increasingly negative ΔV_min is correlated with an increase of strength in hydrogen bonding, which is the opposing trend for the above; this indicates that the 2β-substituents (at least for the heterocyclic class) are dominated by electrostatic factors for binding in-the-stead of the presumptive hydrogen bonding model for this substituent of the cocaine-like binding ligand.^{[lower-alpha 7]}

File:3-R-isoxazol-5-yl.svg

N-methylphenyltropanes with 1R β,β stereochemistry.

Code (S.S. #)	X	R	DA	NE	5HT
RTI-165	Cl	3-methylisoxazol-5-yl	0.59	181	572
RTI-171	Me	3-methylisoxazol-5-yl	0.93	254	3818
RTI-180	I	3-methylisoxazol-5-yl	0.73	67.9	36.4
RTI-177 β-CPPIT 32g	Cl	3-phenylisoxazol-5-yl	1.28 ± 0.18	504 ± 29	2420 ± 136
RTI-176	Me	3-phenylisoxazol-5-yl	1.58	398	5110
RTI-181	I	3-phenylisoxazol-5-yl	2.57	868	100
RTI-184	H	methyl	43.3	—	6208
RTI-185	H	Ph	285	—	>12K
RTI-334	Cl	3-ethylisoxazol-5-yl	0.50	120	3086
RTI-335	Cl	isopropyl	1.19	954	2318
RTI-336	Cl	3-(4-methylphenyl)isoxazol-5-yl	4.09	1714	5741
RTI-337	Cl	3-t-butyl-isoxazol-5-yl	7.31	6321	37K
RTI-345	Cl	p-chlorophenyl	6.42	5290	>76K
RTI-346	Cl	p-anisyl	1.57	762	5880
RTI-347	Cl	p-fluorophenyl	1.86	918	7257
RTI-354	Me	3-ethylisoxazol-5-yl	1.62	299	6400
RTI-366	Me	R = isopropyl	4.5	2523 (1550)	42,900 (3900)
RTI-371	Me	p-chlorophenyl	8.74	>100K (60,200)	>100K (9090)
RTI-386	Me	p-anisyl	3.93	756 (450)	4027 (380)
RTI-387	Me	p-fluorophenyl	6.45	917 (546)	>100K (9400)

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Heterocyclic (N-methyl)phenyltropanes with 1R stereochemistry.

Structure	Code (Singh's #)	X	R	DAT (IC50 nM) displacement of [3 H]WIN 35428	NET (IC50 nM) [3 H]nisoxetine	5-HTT (IC50 nM) [3 H]paroxetine	Script error: No such module "Vertical header".	Script error: No such module "Vertical header".
160px	ααRTI-87	H	3-methyl-1,2,4-oxadiazole	204	36K	30K
160px	βαRTI-119	H	3-methyl-1,2,4-oxadiazole	167	7K	41K
160px	αβRTI-124	H	3-methyl-1,2,4-oxadiazole	1028	71K	33K
170px	RTI-125 (32a)	Cl	3-methyl-1,2,4-oxadiazole	4.05 ± 0.57	363 ± 36	2584 ± 800	637	89.6
145px	ββRTI-126[18] (31)	H	3-methyl-1,2,4-oxadiazole	100 ± 6	7876 ± 551	3824 ± 420	38.3	788
170px	RTI-130 (32c)	Cl	3-phenyl-1,2,4-oxadiazole	1.62 ± 0.02	245 ± 13	195 ± 5	120	151
170px	RTI-141 (32d)	Cl	3-(p-anisyl)-1,2,4-oxadiazole	1.81 ± 0.19	835 ± 8	337 ± 40	186	461
170px	RTI-143 (32e)	Cl	3-(p-chlorophenyl)-1,2,4-oxadiazole	4.06 ± 0.22	40270 ± 180 (4069)	404 ± 56	99.5	9919
170px	RTI-144 (32f)	Cl	3-(p-bromophenyl)-1,2,4-oxadiazole	3.44 ± 0.36	1825 ± 170	106 ± 10	30.8	532
170px	βRTI-151 (33)	Me	3-phenyl-1,2,4-oxadiazole	2.33 ± 0.26	60 ± 2	1074 ± 130	459	25.7
160px	αRTI-152	Me	3-phenyl-1,2,4-oxadiazole	494	—	1995
170px	RTI-154 (32b)	Cl	3-isopropyl-1,2,4-oxadiazole	6.00 ± 0.55	135 ± 13	3460 ± 250	577	22.5
160px	RTI-155	Cl	3-cyclopropyl-1,2,4-oxadiazole	3.41	177	4362

N-methylphenyltropanes with 1R β,β stereochemistry.

Structure	Code	X	2 Group	DAT (IC50 nM) displacement of [3 H]WIN 35428	NET (IC50 nM) displacement of [3 H]nisoxetine	5-HTT (IC50 nM) displacement of [3 H]paroxetine	Selectivity 5-HTT/DAT	Selectivity NET/DAT
150px	RTI-157	Me	tetrazole	1557	>37K	>43K
170px	RTI-163	Cl	tetrazole	911	—	5456
170px	RTI-178	Me	5-phenyl-oxazol-2-yl	35.4	677	1699
170px	RTI-188	Cl	5-phenyl-1,3,4-oxadiazol-2-yl	12.6	930	3304
170px	RTI-189 (32i)	Cl	5-phenyl-oxazol-2-yl	19.7 ± 1.98	496 ± 42	1120 ± 107	56.8	25.5
170px	RTI-194	Me	5-methyl-1,3,4-oxadiazol-2-yl	4.45	253	4885
170px	RTI-195	Me	5-phenyl-1,3,4-oxadiazol-2-yl	47.5	1310	>22,000
170px	RTI-199	Me	5-phenyl-1,3,4-thiadiazol-2-yl	35.9	>24,000	>51,000
170px	RTI-200	Cl	5-phenyl-1,3,4-thiadiazol-2-yl	15.3	4142	>18,000
170px	RTI-202	Cl	benzothiazol-2-yl	1.37	403	1119
170px	RTI-219	Cl	5-phenylthiazol-2-yl	5.71	8516	10,342
	RTI-262	Cl		188.2 ± 5.01	595.25 ± 5738	5207 ± 488	316	28
170px	RTI-370	Me	3-(p-cresyl)isoxazol-5-yl	8.74	6980	>100K
170px	RTI-371	Cl	3-(p-chlorophenyl)isoxazol-5-yl	13	>100K	>100K
170px	RTI-436	Me	-CH=CHPh[20]	3.09	1960 (1181)	335 (31)
170px	RTI-470	Cl	o-Cl-benzothiazol-2-yl	0.094	1590 (994)	1080 (98)
170px	RTI-451	Me	benzothiazol-2-yl	1.53	476 (287)	7120 (647)
170px	32g			1.28 ± 0.18	504 ± 29	2420 ± 136	1891	394
170px	32h			12.6 ± 10.3	929 ± 88	330 ± 196	262	73.7

N.B There are some alternative ways of making the tetrazole ring however; Cf. the sartan drugs synthesis schemes. Bu₃SnN₃ is a milder choice of reagent than hydrogen azide (cf. Irbesartan).

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  Indolyl^[21]
  cf. the Tamagnan series of phenyltropanes for examples with a methylene unit spacer breaking up the indole.

Template:Sort-under

# (#)	X	Y	2 Position	config	8	DA	5-HT	NE
WF-23 (39n)	β-naphthyl		C(O)Et	β,β	NMe	0.115	0.394	No data
WF-31 PIT	-Pri	H	C.O.Et	β,β	NMe	615	54.5	No data
WF-11✲ PTT (39e)	Me	H	-C.O.Et	β,β	NMe	8.2	131	No data
WF-25 (39a)	H	H	-C.O.Et	β,β	NMe	48.3	1005	No data
WF-33	6-MeoBN		C(O)Et	α,β	NMe	0.13	2.24	No data
✲Compound WF-11 has been shown, under consistent exposure, to elicit a biological response opposite of cocaine i.e. tyrosine hydroxylase gene expression down-regulation (instead of up-regulation as has been observed to be the case for chronic cocaine administration)

2β-acyl-3β-phenyltropane structures^{[lower-alpha 8]}

Structure	S. Singh's alphanumeric assignation (name)	R1	R2	DAT [125I]RTI-55 IC50 (nM)	5-HTT [3H]Paroxetine Ki (nM)	Selectivity 5-HTT/DAT
	cocaine			173 ± 19	—	—
	Troparil 11a (WIN 35065–2)			98.8 ± 12.2	—	—
x100px	WF-25 39a	C2H5	C6H5	48.3 ± 2.8	1005 ± 112	20.8
x100px	39b	CH3	C6H5	114 ± 22	1364 ± 616	12.0
x100px	39c	C2H5	C6H4-4-F	15.3 ± 2.8	630 ± 67	41.2
x100px	39d	CH3	C6H4-4-F	70.8 ± 13	857 ± 187	12.1
x100px	WF-11 39e	C2H5	C6H4-4-CH3	8.2 ± 1.6	131 ± 1	16.0
	(+)-39e	C2H5	C6H4-4-CH3	4.21 ± 0.05	74 ± 12	17.6
	(-)-39e	C2H5	C6H4-4-CH3	1337 ± 122	>10000	—
x100px	39f	CH3	C6H4-4-CH3	9.8 ± 0.5	122 ± 22	12.4
x100px	39g	CH3	C6H4-4-C2H5	152 ± 24	78.2 ± 22	0.5
x100px	39h	C2H5	C6H4-4-CH(CH3)2	436 ± 41	35.8 ± 4.4	0.08
x100px	39i	C2H5	C6H4-4-C(CH3)3	2120 ± 630	1771 ± 474	0.8
x100px	39j	C2H5	C6H4-4-C6H5	2.29 ± 1.08	4.31 ± 0.01	1.9
x130px	39k	C2H5	C6H4-2-CH3	1287 ± 322	710000	>7.8
x130px	39l	C2H5	1-naphthyl	5.43 ± 1.27	20.9 ± 2.9	3.8
x130px	39m	CH3	1-naphthyl	10.1 ± 2.2	25.6 ± 5.1	2.5
x100px	WF-23 39n	C2H5	2-naphthyl	0.115 ± 0.021	0.394 ± 0.074	3.5
x100px	39o	CH3	2-naphthyl	0.28 ± 0.11	1.06 ± 0.36	3.8
x100px	39p	C2H5	C6H4-4-CH(C2H5)2	270 ± 38	540 ± 51	2.0
x100px	39q	C2H5	C6H4-4-C6H11	320 ± 55	97 ± 12	0.30
x100px	39r	C2H5	C6H4-4-CH=CH2	0.90 ± 0.34	3.2 ± 1.3	3.5
x100px	39s	C2H5	C6H4-4-C(=CH2)CH3	7.2 ± 2.1	0.82 ± 0.38	0.1

2β-Acyl-3β-(substituted naphthyl)-8-azabicyclo[3.2.1]octanes^[22]

Structure	Short Assignation (Numeric code, Davies UB) S. Singh	R	DAT [125H]RTI-55ɑ IC50 nM	SERT [3H]paroxetineb Ki nM	NET [3H]nisoxetinec Ki nM	potency ratio SERT/DAT	potency ratio SERT/NET
File:WF-11.svg	WF-11 (6)	4′-Me	8.2 ± 1.6	131 ± 10	65 ± 9.2	0.06	0.5
File:WF-31.svg	WF-31 (7)	4′-iPr	436 ± 41	36 ± 4	>10,000	12	>250
File:WF-23.svg	WF-23 (8)	2-naphthalene	0.12 ± 0.02	0.39 ± 0.07	2.9 ± 0.5	0.3	7
x150px	2β-acyl-3β-1-naphthalene (9a)	4′-H	5.3 ± 1.3	21 ± 2.9	49 ± 10	0.3	18
x150px	(9b)	4′-Me	25.1 ± 0.5	8.99 ± 1.70	163 ± 36	3	18
x150px	(9c)	4′-Et	75.1 ± 11.9	175 ± 25	4769 ± 688	0.7	27
x150px	(9d)	4′-iPr	225 ± 36	136 ± 64	>10,000	2	>73.5
x110px	(10a)	6′-Et	0.15 ± 0.04	0.38 ± 0.19	27.7 ± 9.6	0.4	74
x110px	(10b)	6′-iPr	0.39 ± 0.04	1.97 ± 0.33	no data	0.2	—
x110px	(10ce)	6′- OMe	0.13 ± 0.04	2.24 ± 0.34	no data	0.05	—
x110px	(10d)	5′-Et, 6′-OMe	30.8 ± 6.6	7.55 ± 1.57	3362 ± 148	4.1	445
x110px	(10e)	5′-C(Me)=CH2, 6′-OMe	45.0 ± 3.7	88.0 ± 13.3	2334 ± 378	0.5	26.5
x110px	(10f)	6′-I	0.35 ± 0.07	0.37 ± 0.02	no data	1.0	—
x120px	(10g)	7′-I	0.45 ± 0.05	0.47 ± 0.02	no data	0.5d	—
x110px	(10h)	5′-NO2, 6′-OMe	148 ± 50	15 ± 1.6	no data	10	—
x110px	(10i)	5′-I, 6′-OMe	1.31 ± 0.33	2.27 ± 0.31	781 ± 181	0.6	344
x110px	(10j)	5′-COMe, 6′-OMe	12.6 ± 3.8	15.8 ± 1.65	498 ± 24	0.8	32
x145px	(11a)	2β-COCH3, 1-naphthyl	10 ± 2.2	26 ± 5.1	165 ± 40	0.4	6.3
x135px	(11b)	2α-COCH3, 1-naphthyl	97 ± 21	217 ± 55	no data	0.45	—
x120px	(11c)	2α-COCH2CH3, 2-naphthyl	2.51 ± 0.82	16.4 ± 2.0	68.0 ± 10.8	0.15	4.1
x110px	(11d)	2β-COCH3, 2-naphthyl	1.27 ± 0.15	1.06 ± 0.36	4.9 ± 1.2	1.2	4.6
x110px	(11e)	2β-COCH(CH3)2, 2-naphthyl	0.25 ± 0.08	2.08 ± 0.80	37.6 ± 10.5	0.12	18.1
x110px	(11f) 79a	2β-COCH2CH3, 2-naphthyl, N8-demethyl	0.03 ± 0.01	0.23 ± 0.07	2.05 ± 0.9	0.13	8.9

ɑ nonspecific binding was determined in the presence of 1.0 μM WF-23 (source equates WF-23 as analogue 3a, but table gives # as analogue 8) b nonspecific binding was determined in the presence of 10.0 μM fluoxetine

c nonspecific binding was determined in the presence of 1.0 μM desipramine d ratio shown as halved; a possible copy-error due to closeness to 1:1 of other indicated values e sources differ on whether C2 position acyl is alpha or beta configured

Note: p-fluorophenyl is weaker than the others. RTI-145 is not peroxy, it is a methyl carbonate.

Code	X	2 Position	config	8	DA	5-HT	NE
RTI-100	F	-CH2OH	β,β	NMe	47	4741	no data
RTI-101	I	-CH2OH	β,β	NMe	2.2	26	no data
RTI-99	Br	-CH2OH	β,β	NMe	1.49	51	no data
RTI-93	Cl	-CH2OH	β,β	NMe	1.53	204	43.8
RTI-105	Cl	-CH2OAc	β,β	NMe	1.60	143	127
RTI-123	Cl	-CH2OBz	β,β	NMe	1.78	3.53	393
RTI-145	Cl	-CH2OCO2Me	β,β	NMe	9.60	2.93	1.48

2-Alkane/Alkene-3-Phenyltropanes

Structure	Singh's #	R	X	DAT mazindol displacement	DA uptake	5-HT Uptake	Selectivity DA uptake/DAT binding
	11a WIN 35062-2			89.4	53.7	186	0.6
	11c			0.83 ± 00.7	28.5 ± 0.9	—	34.3
	11f			5.76	6.92	23.2	1.2
	41a	(CH2)2CH3	H	12.2	6.89	86.8	0.6
	41b	(CH2)3C6H5	H	16 ± 2a	43 ± 13b	—	2.7
	42	(CH2)2CH3	F	5.28	1.99	21.7	0.4
	43a	CH=CH2	Cl	0.59 ± 0.15	2.47 ± 0.5	—	4.2
	43b	E-CH=CHCl	Cl	0.42 ± 0.04	1.13 ± 0.27	—	2.7
	43c	Z-CH=CHCl	Cl	0.22 ± 0.02	0.88 ± 0.05	—	4.0
	43d	E-CH=CHC6H5	Cl	0.31 ± 0.04	0.66 ± 0.01	—	2.1
	43e	Z-CH=CHC6H5	Cl	0.14 ± 0.07	0.31 ± 0.09	—	2.2
	43f	CH2CH3	Cl	2.17 ± 0.20	2.35 ± 0.52	—	1.1
	43 g	(CH2)2CH3	Cl	0.94 ± 0.08	1.08 ± 0.05	—	1.1
	43h	(CH2)3CH3	Cl	1.21 ± 0.18	0.84 ± 0.05	—	0.7
	43i	(CH2)5CH3	Cl	156 ± 15	271 ± 3	—	1.7
	43j	(CH2)2C6H5	Cl	1.43 ± 0.03	1.54 ± 0.08	—	1.0
	44a	(CH2)2CH3	CH3	1.57	1.10	10.3	0.7
	44b	(CH2)3CH3	CH3	1.82	1.31	15.1	0.7
	45	(CH2)2CH3	H	74.9	30.2	389	0.4
	46	(CH2)2CH3	F	21.1	12.1	99.6	0.6
	47a	(CH2)2CH3	CH3	8.91	11.8	50.1	1.3
	47b	(CH2)3CH3	CH3	11.4	10.1	51.0	0.9

^aK_i value for displacement of WIN 35428.
^bIC₅₀ value.

300px
Irreversible (phenylisothiocyanate) binding ligand (Murthy, V.; Martin, T. J.; Kim, S.; Davies, H. M. L.; Childers, S. R. (2008). "In Vivo Characterization of a Novel Phenylisothiocyanate Tropane Analog at Monoamine Transporters in Rat Brain". Journal of Pharmacology and Experimental Therapeutics 326 (2): 587–595. doi:10.1124/jpet.108.138842. PMID 18492949. )^[23] RTI-76:^[24] 4′-isothiocyanatophenyl (1R,2S,3S,5S)-3-(4-chlorophenyl)-8-methyl-8-azabicyclo[3.2.1]octane-2-carboxylate. Also known as: 3β-(p-chlorophenyl)tropan-2β-carboxylic acid p-isothiocyanatophenylmethyl ester.

x170px
HD-205 (Murthy et al., 2007)^[25]

Note the contrast to the phenylisothiocyanate covalent binding site locations as compared to the one on p-Isococ, a non-phenyltropane cocaine analogue.

500px280px

2-(Diarylmethoxymethyl)-3β-aryltropanes & 2β-[3-(Diarylmethoxy)propyl]-3β-aryltropanes.^[26][27]

Structure	Compound	R	X	Y	[3H]WIN 35,428 @ DAT Ki (nM)	[3H]Citalopram @ SERT Ki (nM)	[3H]Nisoxetine @ NET Ki (nM)	[3H]Pirenzepine @ M1 Ki (nM)
200px
	9a	CH3	H	H	34 ± 2	121 ± 19	684 ± 100	10,600 ± 1,100
	9b	F	H	H	49 ± 12	—	—	—
	9c	Cl	H	H	52 ± 2.1	147 ± 8	1,190 ± 72	11,000 ± 1,290
	9d	CH3	Cl	H	80 ± 9	443 ± 60	4,400 ± 238	31,600 ± 4,300
	9e	F	Cl	H	112 ± 11	—	—	—
	9f	Cl	Cl	H	76 ± 7	462 ± 36	2,056 ± 236	39,900 ± 5,050
	9g	CH3	F	F	62 ± 7	233 ± 24	1,830 ± 177	15,500 ± 1,400
	9h	F	F	F	63 ± 13	—	—	—
	9i	Cl	F	F	99 ± 18	245 ± 16	2,890 ± 222	16,300 ± 1,300
200px
	10a	CH3	H	H	455 ± 36	530 ± 72	2,609 ± 195	12,600 ± 1,790
	10c	Cl	H	H	478 ± 72	408 ± 16	3,998 ± 256	11,500 ± 1,720
	10d	CH3	Cl	H	937 ± 84	1,001 ± 109	22,500 ± 2,821	18,200 ± 2,600
	10f	Cl	Cl	H	553 ± 106	1,293 ± 40	5,600 ± 183	9,600 ± 600
	10g	CH3	F	F	690 ± 76	786 ± 67	16,000 ± 637	9,700 ± 900
	10i	Cl	F	F	250 ± 40	724 ± 100	52,300 ± 13,600	9,930 ± 1,090
200px
	12a	H	H	H	139 ± 15	61 ± 9	207 ± 30	7,970 ± 631
	12b	H	Cl	H	261 ± 19	45 ± 3	—	24,600 ± 2,930
	12c	H	F	F	60 ± 7	—	—	—

One patent claims a series of compounds with biotin-related sidechains are pesticides.^[18]

Images of the biotin C2 side-chained phenyltropanes, click to
x170px x170px x170px x170px x240px x200px x290px x290px x280px x240px x200px x200px x260px x260px

Structure	Code	para-X	C2-Tropane Position	config	DA	NE	5-HT
x150px	—	H	F1	β,β	—	—	—
x140px	RTI-224	Me	F1c	β,β	4.49	—	155.6
x160px	RTI-233	Me	F2	β,β	4.38	516	73.6
x160px	RTI-235	Me	F3d	β,β	1.75	402	72.4
x150px	—	—	F3	β,β	—	—	—
x140px	RTI-236	Me	B1d	β,β	1.63	86.8	138
x140px	RTI-237	Me	B2d	β,β	7.27	258	363
x160px	RTI-244	Me	B3d	β,β	15.6	1809	33.7
x140px	RTI-245	Cl	F4c	β,β	77.3	—	—
	RTI-246	Me	F4c	β,β	50.3	3000	—
x150px	—	—	F5	β,β	—	—	—
x120px	RTI-248	Cl	F6c	β,β	9.73	4674	6.96
x140px	RTI-249	Cl	F1c	β,β	8.32	5023	81.6
	RTI-266	Me	F2	β,β	4.80	836	842
	RTI-267	Me	F7 wrong	β,β	2.52	324	455
x210px	RTI-268	Me	F7 right	β,β	3.89	1014	382
x220px	RTI-269	Me	F8	β,β	5.55	788	986

800px 800px

Structure	Code	X	2 Position	config	8	DA	5-HT	NE
170px	RTI-102	I	CO2H	β,β	NMe	474	1928	43,400
170px	RTI-103	Br	CO2H	β,β	NMe	278	3070	17,400
170px	RTI-104	F	CO2H	β,β	NMe	2744	>100K	>100K
170px	RTI-108	Cl	-CH2Cl	β,β	NMe	2.64	98	129.8
170px	RTI-241	Me	-CH2CO2Me	β,β	NMe	1.02	619	124
170px	RTI-139	Cl	-CH3	β,β	NMe	1.67	85	57
170px	RTI-161	Cl	-C≡N	β,β	NMe	13.1	1887	2516
170px	RTI-230	Cl	H3C–C=CH2	β,β	NMe	1.28	57	141
170px	RTI-240	Cl	-CHMe2	β,β	NMe	1.38	38.4	84.5
170px	RTI-145	Cl	-CH2OCO2Me	β,β	NMe	9.60	2,932	1,478
170px	RTI-158	Me	-C≡N	β,β	NMe	57	5095	1624
170px	RTI-131	Me	-CH2NH2	β,β	NMe	10.5	855	120
170px	RTI-164	Me	-CH2NHMe	β,β	NMe	13.6	2246	280
170px	RTI-132	Me	-CH2NMe2	β,β	NMe	3.48	206	137
170px	RTI-239	Me	-CHMe2	β,β	NMe	0.61	114	35.6
180px	RTI-338	Et	-CO2CH2Ph	β,β	NMe	1104	7.41	3366
150px	RTI-348	H	-Ph	β,β	NMe	28.2	>34,000	2670

Peters, Dan; Gunnar M. Olsen & Elsebet Oestergaard Nielsen et al., "Aza-ring derivatives and their use as monoamine neurotransmitter re-uptake inhibitors", WO patent 2004113297, published 2004-12-29

Test compound	DA-uptake IC50(μM)	NA-uptake IC50(μM)	5-HT-uptake IC50(μM)
(+)-3-(4-Chlorophenyl)-8-H-aza-bicyclo[3.2.1]oct-2-ene	0.26	0.028	0.010
(+)-3-Napthalen-2-yl-8-azabicyclo[3.2.1]oct-2-ene	0.058	0.013	0.00034
(–)-8-Methyl-3-(naphthalen-2-yl)-8-azabicylo[3.2.1]oct-2-ene	0.034	0.018	0.00023

8-AZABICYCLO[3.2.1]OCT-2-ENE DERIVATIVES

Test Compound	DA uptake IC50(μM)	NE uptake IC50(μM)	5-HT uptake IC50(μM)
(±)-3-(3,4-Dichlorophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene	0.079	0.026	0.0047

U.S. Patent 2,001,047,028

Test Compound	DA uptake IC50(μM)	NE uptake IC50(μM)	5-HT uptake IC50(μM)
(±)-3-(4-cyanophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene	18	4.9	0.047
(±)-3-(4-nitrophenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene	1.5	0.5	0.016
(±)-3-(4-trifluoromethoxyphenyl)-8-methyl-8-azabicyclo[3.2.1]oct-2-ene	22.00	8.00	0.0036

Structure 100px	Compound (RTI #) (S. Singh's #)	X	2 Group	config	8	DAT IC50 (nM) [3H]WIN 35428	5-HTT IC50 (nM) [3H]paroxetine	NET IC50 (nM) [3H]nisoxetine	selectivity 5-HTT/DAT	selectivity NET/DAT
100px	RTI-140 20a	H	CO2Me	β,α	NMe	101 ± 16	5,701 ± 721	2,076 ± 285	56.4	20.6
100px	RTI-352ɑ 20d	I	CO2Me	β,α	NMe	2.86 ± 0.16	64.9 ± 1.97	52.4 ± 4.9	22.8	18.4
100px	RTI-549	Br	CO2Me	β,α	NMe	—	—	—	—	—
100px	RTI-319b	3α-2-naphthyl	CO2Me	β,α	NMe	1.1 ± 0.09	11.4 ± 1.3	70.2 ± 6.28	—	—
100px	RTI-286c 20b	F	CO2Me	β,α	NMe	21 ± 0.57	5062 ± 485	1231 ± 91	241	58.6
140px	RTI-274d	F	CH2O(3′,4′-MD-phenyl)	β,α	NH	3.96	5.62	14.4	—	—
100px	RTI-287	Et	CO2Me	β,α	NMe	327	1687	17,819	—	—
100px	20c	Cl	CO2Me	β,α	NMe	2.4 ± 0.2	998 ± 120	60.1 ± 2.4	416	25.0
100px	20e	Me	CO2Me	β,α	NMe	10.2 ± 0.08	4250 ± 422	275 ± 24	417	27.0
120px		Bn	CO2Me	β,α	NMe	—	—	—	—	—

800px

CA patent 2112084

• 
• 
• 

Compound	DA (μM)	M.E.D. (mg/kg)	Dose (mg/kg)	Activity	Activity
(2R,3S)-2-(4-chlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane	0.39	<1	50	0	0
(2R,3S)-2-(carboxymethyl)-8-methyl-3-(2-naphthyl)-8-azabicyclo[3.2.1]octane	0.1	1	25	0	0
(2R,3S)-2-(carboxymethyl)-8-methyl-3-(3,4-dichlorophenyl)-8-azabicyclo[3.2.1]octane	0.016	0.25	50	+	+++

U.S. Patent 2,001,047,028

Compound	X	2 Group	config	8	DA	5-HT	NE
Brasofensine	Cl2	methyl aldoxime	α,β	NMe	—	—	—
Tesofensine	Cl2	ethoxymethyl	α,β	NMe	65	11	1.7
NS-2359 (GSK-372,475)	Cl2	Methoxymethyl	α,β	NH	—	—	—

Peters, Dan; Elsebet Oestergaard Nielsen & Gunnar M. Olsen et al., "Novel 8-aza-bicyclo[3.2.1]octane derivatives and their use as monoamine neurotransmitter re-uptake inhibitors", WO patent 2004072075, published 2004-08-26

Test Compound	DA uptake IC50(μM)	NE uptake IC50(μM)	5-HT uptake IC50(μM)
(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt	0.062	0.035	0.00072
(2R,3S)-2-(Naphthaleneoxymethane)-8-methyl-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt	0.062	0.15	0.0063
(2R,3S)-2-(2,3-dichlorophenoxymethyl)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt	0.10	0.048	0.0062
(2R,3S)-2-(Naphthlyloxymethane)-8-H-3-(3-chlorophenyl)-8-azabicyclo[3.2.1]octane fumaric acid salt	0.088	0.051	0.013

Unlike metal complexed PTs created with the intention of making useful radioligands, 21a & 21b were produced seeing as their η⁶-coordinated moiety dramatically altered the electronic character and reactivity of the benzene ring, as well as such a change adding asymmetrical molecular volume to the otherwise planar arene ring unit of the molecule.^[1] (cf. the Dewar–Chatt–Duncanson model). In addition the planar dimension of the transition metal stacked arene becomes delocalized (cf. Bloom and Wheeler.^[29]).

21a was twice as potent as both cocaine and troparil in displacement of β-CFT, as well as displaying high & low affinity K_i values in the same manner as those two compounds. Whereas its inhibition of DA uptake showed it as comparably equipotent to cocaine & troparil. 21b by contrast had a one hundredfold decrease in high-affinity site binding compared to cocaine and a potency 10× less for inhibiting DA uptake. Attesting these as true examples relating useful effective applications for bioorganometallic chemistry.

The discrepancy in binding for the two benzene metal chelates is assumed to be due to electrostatic differences rather than their respective size difference. The solid cone angles, measured by the steric parameter (i.e. θ) is θ=131° for Cr(CO)₃ whereas Cp*Ru was θ=187° or only 30% larger. The tricarbonyl moiety being considered equivalent to the cyclopenta dienyl (Cp) ligand.^[1]

Displacement of Receptor-Bound [³H]WIN 35428 and Inhibition of [³H]DA Uptake by Transition Metal Complexes of 3β-Phenyltropanes^[1]

Structure	Compound # (S. Singh) Systematic name	Ki (nM)ɑ	IC50 (nM)	selectivity binding/uptake
	21ac	17 ± 15b 224 ± 83	418	24.6
	21bd	2280 ± 183	3890	1.7
Cocaine		32 ± 5 388 ±221	405	12.6
Troparil (11a)		33 ± 17 314 ± 222	373	11.3

• ^ɑThe binding data fit a two-site model better than a one-site model
• ^bThe K_i value for the one-site model was 124 ± 10 nM
• ^cIUPAC: [η⁶-(2β-carbomethoxy-3β-phenyl)tropane]tricarbonylchromium
• ^dIUPAC: [η⁵-(pentamethylcyclopentadienyl)]-[η⁶-(2β-carbomethoxy-3β-phenyl)tropane]ruthenium-(II) triflate

Code	Compound	DA (μM)	NE (μM)	5-HT (μM)
1	(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octanefumaric acid salt	0.30	0.0019	0.00052
2	(2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-thienyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt	0.36	0.0036	0.00042
3	(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt	0.31	0.00090	0.00036
4	(2R,3S)-2-(1-Naphthyloxymethyl)-8-methyl-3-(2-furanyl)-8-aza-bicyclo-[3.2.1]octane fumaric acid salt	0.92	0.0030	0.00053
5	(2R,3S)-2-(2,3-Dichlorophenoxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt	0.074	0.0018	0.00074
6	(2R,3S)-2-(1-Naphthyloxymethyl)-8-H-3-(2-thienyl)-8-aza-bicyclo[3.2.1]octane fumaric acid salt	0.19	0.0016	0.00054

800px

• 
  Fluoxetine homologue,^[30] also: Hanna et al. (2007)^[31]
  cf. the paroxetine homologue PTs
• 
  ZIENT:^[32]

6/7-Substituted 2-carbomethoxy-phenyltropanes^[1]

Structure	Compound # (S. Singh)	Substitution	DAT (IC50 nM) displacement of [H3]WIN 35428	5-HTT (IC50 nM) [H3]Citalopram	Selectivity 5-HTT/DAT
	Cocaine	H	65 ± 12	-	-
160px	103a	3β,2β, 7-OMe 3′,4′-Cl2	86 ± 4.7	884 ± 100	10.3
160px	103b	3β,2β, 7-OH 3′,4′-Cl2	1.42 ± 0.03	28.6 ± 7.8	20.1
130px	103c	3α,2β, 7-OH 3′,4′-Cl2	1.19 ± 0.16	1390 ± 56	1168
160px	104a	3β,2β, 6-OH 4′-Me	215ɑ	-	-
160px	104b	3β,2α, 6-OH 4′-Me	15310ɑ	-	-
130px	104c	3α,2β, 6-OH 4′-Me	930ɑ	-	-
130px	104d	3α,2α, 6-OH 4′-Me	7860ɑ	-	-

• ^ɑIC₅₀ value for displacement of [H³]mazindol. IC₅₀ for cocaine 288 nM for displacement of [H³]mazindol

6/7-Substituted 3-butyl-phenyltropanes^[1]

Structure	Compound # (S. Singh)	Substituent	Ki nM displacement of [H3]mazindol binding	Ki nM [H3]DA uptake	Selectivity uptake/binding
	Cocaine	H	270 ± 0.03	400 ± 20	1.5
x70px	121a	7β-CN	2020 ± 10	710 ± 40	0.3
x70px	121b	6β-CN	3040 ± 480	6030 ± 880	2.0
x70px	121c	7β-SO2Ph	4010 ± 310	8280 ± 1340	2.1
x90px	121d	6β-SO2Ph	4450 ± 430	8270 ± 690	1.8
x80px	121e	7α-OH	830 ± 40	780 ± 60	0.9
x130px	121f	H	100 ± 10	61 ± 10	0.6
x130px	121g	7β-CN	24000 ± 3420	32100 ± 8540	1.3
x130px	121h	6β-CN	11300 ± 1540	26600 ± 3330	2.3
x130px	121i	7β-SO2Ph	7690 ± 2770	7050 ± 450	0.9
x130px	121j	6β-SO2Ph	4190 ± 700	8590 ± 1360	2.0
x130px	121k	7α-SO2Ph	3420 ± 1100	-	-
x130px	121l	7β-SO2Ph, 7α-F	840 ± 260	2520 ± 290	3.0
x130px	121m	7α-F	200 ± 10	680 ± 10	3.4
x130px	121n	7β-F	500 ± 10	550 ± 140	1.1

6/7-synthetic intermediates^[1]

Structure	Compound # (S. Singh)	Substituent W	Substituent X	Substituent Y	Substituent Z
x120px	(±)-122a	CN	H	H	H
x120px	(±)-122b	H	H	CH	H
x120px	(±)-122c	H	CH	H	H
x120px	(±)-122d	H	H	H	CH
x120px	(±)-122e	SO2Ph	H	H	H
x120px	(±)-122f	H	H	SO2Ph	H
x120px	(±)-122g	H	SO2Ph	H	H
x120px	(±)-122h	SO2Ph	F	H	H
x120px	(±)-122i	F	SO2Ph	H	H
x120px	(±)-122j	H	H	SO2Ph	F

It is well established that electrostatic potential around the para position tends to improve MAT binding. This is believed to also be the case for the meta position, although it is less studied. N-demethylation dramatically potentiates NET and SERT affinity, but the effects of this on DAT binding are insignificant.^[33] Of course, this is not always the case. For an interesting exception to this trend, see the Taxil document. There is ample evidence suggesting that N-demethylation of alkaloids occurs naturally in vivo via a biological enzyme. The fact that hydrolysis of the ester leads to inactive metabolites means that this is still the main mode of deactivation for analogues that have an easily metabolised 2-ester substituent. The attached table provides good illustration of the effect of this chemical transformation on MAT binding affinities. N.B. In the case of both nocaine and pethidine, N-demethyl compounds are more toxic and have a decreased seizure threshold.^[34]

Selected ββ Nortropanes

Code (S.S. #)	X para (unless position otherwise given inline)	DA	5HT	NE
RTI-142 75b	F	4.39	68.6	18.8
RTI-98 75d Norɑ-RTI-55	I	0.69	0.36	11.0
RTI-110 75c	Cl	0.62	4.13	5.45
RTI-173 75f	Et	49.9	8.13	122
RTI-279 Norɑ-RTI-280	para-Me meta-I	5.98 ± 0.48	1.06 ± 0.10	74.3 ± 3.8
RTI-305 Norɑ-RTI-360/11y	Ethynyl	1.24 ± 0.11	1.59 ± 0.2	21.8 ± 1.0
RTI-307 Norɑ-RTI-281/11z	Propynyl	6.11 ± 0.67	3.16 ± 0.33	115.6 ± 5.1
RTI-309 Norɑ-11t	Vinyl	1.73 ± 0.05	2.25 ± 0.17	14.9 ± 1.18
RTI-330 Norɑ-11s	Isopropyl	310.2 ± 21	15.1 ± 0.97	—
RTI-353	para-Et meta-I	330.54 ± 17.12	0.69 ± 0.07	148.4 ± 9.15

^ɑThe N-demethylated variant of (i.e. compound code-name after dash)

N-demethylating various β,β p-HC-phenyltropanes

N-Me compound code# → N-demethylated derivative compound code #	para-X	[3H]Paroxetine	[3H]WIN 35,428	[3H]Nisoxetine
11 g→75f	Ethyl	28.4 → 8.13	55 → 49.9	4,029 → 122
11t→75i	Vinyl	9.5 → 2.25	1.24 → 1.73	78 → 14.9
11y→75n	Ethynyl	4.4 → 1.59	1.2 → 1.24	83.2 → 21.8
11r→75 g	1-Propyl	70.4 → 26	68.5 → 212	3,920 → 532
11v→75k	trans-propenyl	11.4 → 1.3	5.29 → 28.6	1,590 → 54
11w→75l	cis-propenyl	7.09 → 1.15	15 → 31.6	2,800 → 147
11x→75 m	Allyl	28.4 → 6.2	32.8 → 56.5	2,480 → 89.7
11z→75o	1-Propynyl	15.7 → 3.16	2.37 → 6.11	820 → 116
11s→75h	i-Propyl	191 → 15.1	597 → 310	75,000 → ?
11u→75j	2-Propenyl	3.13 → 0.6	14.4 → 23	1,330? → 144

N-Demethylating phenyltropanes to find a NRI

Isomer	4′	3′	NE	DA	5HT
β,β	Me	H	60 → 7.2	1.7 → 0.84	240 → 135
β,β	F	H	835 → 18.8	15.7 → 4.4	760 → 68.6
β,β	Cl	H	37 → 5.45	1.12 → 0.62	45 → 4.13
β,α	Me	H	270 → 9	10.2 → 33.6	4250 → 500
β,α	F	H	1200 → 9.8	21 → 32.6	5060 → 92.4
β,α	Cl	H	60 → 5.41	2.4 → 3.1	998 → 53.3
β,α	F	Me	148 → 4.23	13.7 → 9.38	1161 → 69.8
β,α	Me	F	44.7 → 0.86	7.38 → 9	1150 → 97.4

"Interest in NET selective drugs continues as evidenced by the development of atomoxetine, manifaxine, and reboxetine as new NET selective compounds for treating ADHD and other CNS disorders such as depression" (FIC, et al. 2005).^[35]

N-norphenyltropanes^[1]

Structure	Short Name (S. Singh)	Para-X	DAT [3H]WIN 35428 IC50 (nM)	5-HTT [3H]Paroxetine IC50 (nM)	NET [3H]Nisoxetine IC50 (nM)	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	Norcocaine	H	206 ± 29	127 ± 13	139 ± 9	0.6	0.7
x100px	75a	H	30.8 ± 2.3	156 ± 8	84.5 ± 7.5	5.1	2.7
x100px	75b	F	4.39 ± 0.20	68.6 ± 2.0	18.8 ± 0.7	15.6	4.3
x100px	75c	Cl	0.62 ± 0.09	4.13 ± 0.62	5.45 ± 0.21	6.7	8.8
x100px	75d	I	0.69 ± 0.2	0.36 ± 0.05	7.54 ± 3.19	0.5	10.9
x110px	75e	para-I & 2β-CO2CH(CH3)2	1.06 ± 0.12	3.59 ± 0.27	132 ± 5	3.4	124
x100px	75f	C2H5	49.9 ± 7.3	8.13 ± 0.30	122 ± 12	0.2	2.4
x100px	75g	n-C3H7	212 ± 17	26 ± 1.3	532 ± 8.1	0.1	2.5
x100px	75h	CH(CH3)2	310 ± 21	15.1 ± 0.97	-	0.05	-
x100px	75i	CH=CH2	1.73 ± 0.05	2.25 ± 0.17	14.9 ± 1.18	1.3	8.6
x100px	75j	C-CH3 ║ CH2	23 ± 0.9	0.6 ± 0.06	144 ± 12	0.03	6.3
x100px	75k	trans-CH=CHCH3	28.6 ± 3.1	1.3 ± 0.1	54 ± 16	0.04	1.9
x100px	75l	cis-CH=CHCH3	31.6 ± 2.2	1.15 ± 0.1	147 ± 4.3	0.04	4.6
x100px	75m	CH2CH=CH2	56.5 ± 56	6.2 ± 0.3	89.7 ± 9.6	0.1	1.6
x100px	75n	CH≡CH	1.24 ± 0.11	1.59 ± 0.2	21.8 ± 1.0	1.3	17.6
x100px	75o	CH≡CCH3	6.11 ± 0.67	3.16 ± 0.33	116 ± 5.1	0.5	19.0
x110px	75pɑ	3,4-Cl2	0.66 ± 0.24	1.4b	-	2.1	-

^ɑThese values determined in Cynomolgus monkey caudate-putamen ^bThe radioligand used for 5-HTT was [³H]citalopram

2β-Propanoyl-N-norphenyltropanes^[1]

Compound Structure	Short Name (S. Singh)	DAT [125I]RTI-55 IC50 (nM)	5-HTT [3H]Paroxetine Ki (nM)	NET [3H]Nisoxetine Ki (nM)	Selectivity 5-HTT/DAT	Selectivity NET/DAT
x100px	79a	0.07 ± 0.01	0.22 ± 0.16	2.0 ± 0.09	3.1	28.6
x100px	79b	4.7 ± 0.58	19 ± 1.4	5.5 ± 2.0	4.0	1.2
x100px	79c	380 ± 110	5.3 ± 1.0	3400 ± 270	0.01	8.9
x100px	79d	190 ± 17	150 ± 50	5100 ± 220	0.8	26.8
x100px	79e	490 ± 120	85 ± 16	4300 ± 1100	0.1	8.8
x100px	79f	1.5 ± 1.1	0.32 ± 0.06	10.9 ± 1.5	0.2	7.3
x100px	79g	16 ± 4.9	0.11 ± 0.02	94 ± 18	0.07	5.9

See the N-methyl paroxetine homologues cf. di-aryl phenyltropanes for another SSRI approximated hybrid: the fluoxetine based homologue of the phenyltropane class.

2-(3,4-(Methylenedioxy)phenoxy)methyl-norphenyltropane binding potencies^[1]

Compound Structure	Short Name (S. Singh)	Stereochemistry	DAT [3H]WIN 35428 IC50 (nM)	5-HTT [3H]Paroxetine IC50 (nM)	NET [3H]Nisoxetine IC50 (nM)	Selectivity 5-HTT/DAT	Selectivity NET/DAT
x130px	Paroxetine	-	623 ± 25	0.28 ± 0.02	535 ± 15	0.0004	0.8
x130px	R-81a	2β,3β	835 ± 90	480 ± 21	37400 ± 1400	0.6	44.8
x130px	R-81b	2α,3β	142 ± 13	90 ± 3.4	2500 ± 250	0.6	17.6
x180px	R-81c	2β,3α	3.86 ± 0.2	5.62 ± 0.2	14.4 ± 1.3	1.4	3.7
x130px	S-81d	2β,3β	1210 ± 33	424 ± 15	17300 ± 1800	0.3	14.3
x130px	S-81e	2α,3β	27.6 ± 2.4	55.8 ± 5.73	1690 ± 150	2.0	61.2
x180px	S-81f	2β,3α	407 ± 33	19 ± 1.8	1990 ± 176	0.05	4.9

The eight position nitrogen has been found to not be an exclusively necessary functional anchor for binding at the MAT for phenyltropanes and related compounds. Sulfurs, oxygens, and even the removal of any heteroatom, leaving only the carbon skeleton of the structure at the bridged position, still show distinct affinity for the monoamine transporter cocaine-target site and continue to form an ionic bond with a measurable degree of reasonable efficacy.

Compound	X	2 Group	config	8	DA	5-HT	NE
Tropoxane	Cl,Cl	CO2Me	(racemic) β,β	O	3.3	6.5	No data
O-4210[36]	p-F	3-methyl-5-isoxazole	β,β	S	7.0	>1000	No data

8-Oxanortropanes, binding inhibition using monkey caudate-putamen^[1]

Structure	Compound # (S. Singh)	Para- (meta-)	DAT (IC50 nM) displacement of [H3]WIN 35428	5-HTT (IC50 nM) [H3]Citalopram	Selectivity 5-HTT/DAT
120px	R/S-90a	H	>1000	>1000	-
140px	R/S-90b	F	546	2580	4.7
140px	R/S-90c	Cl	10	107	10.7
140px	R/S-90d	Br	22	30	1.4
140px	R/S-90e	I	7	12	1.7
140px	R/S-90f	3,4-Cl2	3.35	6.52	1.9
140px	R-90g	3,4-Cl2	3.27	4.67	1.4
140px	S-90h	3,4-Cl2	47	58	1.2
90px	R/S-91a	H	1990	11440	5.7
90px	R/S-91b	F	>1000	>10000	-
90px	R/S-91c	Cl	28.5	816	28.6
90px	R/S-91d	Br	9	276	30.7
90px	R/S-91e	I	42	72	1.7
100px	R/S-91f	3,4-Cl2	3.08	64.5	20.9
100px	R-91g	3,4-Cl2	2.34	31	13.2
100px	S-91h	3,4-Cl2	56	2860	51.1

8-carba 3-Aryl bicyclo[3.2.1]octanes^[1]

Structure	Compound # (S. Singh)	DAT (IC50 nM) displacement of [H3]WIN 35428	5-HTT (IC50 nM) [H3]Citalopram	Selectivity 5-HTT/DAT
140px	R/S-98a	7.1 ± 1.7	5160 ± 580	726
140px	R/S-98b	9.6 ± 1.8	33.4 ± 0.6	3.5
100px	R/S-98c	14.3 ± 1.1	180 ± 65	12.6

• 
• 
• 

Compound	X	2 Group	config	8	DAT	SERT	NET
FP-β-CPPIT	Cl	3′-phenylisoxazol-5′-yl	β,β	NCH2CH2CH2F	-	-	-
FE-β-CPPIT	Cl	(3′-phenylisoxazol-5′-yl)	β,β	NCH2CH2F	-	-	-
Altropane (IACFT)	F	CO2Me	β,β	NCH2CH=CHF	-	-	-
FECNT[37]	I	CO2Me	β,β	NCH2CH2F	-	-	-
RTI-310 U.S. Patent 5,736,123	I	CO2Me	β,β	N-Prn	1.17	-	-
RTI-311	I	CO2Me	β,β	NCH2CH=CH2	1.79	-	-
RTI-312 U.S. Patent 5,736,123	I	CO2Me	β,β	NBun	0.76	-	-
RTI-313 U.S. Patent 5,736,123	I	CO2Me	β,β	NCH2CH2CH2F	1.67	-	-
Ioflupane (FP-CIT)	123I	CO2Me	β,β	NCH2CH2CH2F	-	-	-
PE2I[37]	Me	CO2Me	β,β	NCH2CH=CHI	-	-	-
RTI-251	Cl	CO2Me	β,β	NCH2CO2Et	1.93	10.1	114
RTI-252	Cl	CO2Me	β,β	NCH2CH2CO2Et	2.56	35.2	125
RTI-242	Cl	β,β (bridged) -C(O)CH(CO2Me)CH2N			7.67	227	510

Bi- and tri-cyclic aza compounds and their uses.^[38][39]

N-substituted 3β-phenylnortropanes^[1]
(including N-phthalimidoalkyl analogues of β-CIT)

Structure	Short Name (S. Singh)	Nitrogen side-chain (N8)	DAT [3H]GBR 12935 Ki (nM)	5-HTT [3H]Paroxetine Ki (nM)	NET [3H]Nisoxetine Ki (nM)	Selectivity 5-HTT/DAT	Selectivity NET/DAT
	Cocaine	H	350 ± 80	>10000	>30000	>28.6	-
	GBR 12909	-	0.06 ± 0.02	52.8 ± 4.4	>20000	880	-
	WIN 35428 11b	H	14.7 ± 2.9	181 ± 21	635 ± 110	12.3	43.2
	RTI-55 11e	H	1.40 ± 0.20	0.46 ± 0.06	2.80 ± 0.40	0.3	2
150px	82a	CH2CH=CH2	22.6 ± 2.9ɑ	-	-	-	-
150px	82b	CH2CH2CH3	43.0 ± 17.7ɑ	-	-	-	-
160px	82c	CH2C6H5	58.9 ± 1.65b	1073c	-	18.2	-
200px	82d	(CH2)3C6H5	1.4 ± 0.2b	133 ± 7c	-	95.0	-
210px	82e	(CH2)5C6H5	3.4 ± 0.83b	49.9 ± 10.2c	-	14.7	-
160px	83a	CH2CH2CH2F	1.20 ± 0.29	48.7 ± 8.4	10000	40.6	8333
160px	83b	CH2CH2F	4.40 ± 0.35	21.7 ± 8.3	>10000	4.9	-
160px	84a	CH2CH2CH2F	3.50 ± 0.39	0.110 ± 0.02	63.0 ± 4.0	0.03	18
160px	84b	CH2CH2F	4.00 ± 0.73	0.140 ± 0.02	93.0 ± 17.0	0.03	23.2
160px	84c	CH2CHF2	15.1 ± 3.7	9.6 ± 1.5	>5000	0.6	-
170px	84d	CH2CH2CH2Cl	3.10 ± 0.57	0.32 ± 0.06	96.0 ± 29.0	0.1	31.0
170px	84e	CH2CH2CH2Br	2.56 ± 0.57	0.35 ± 0.08	164 ± 47	0.1	64.1
170px	84f	CH2CH2CH2I	38.9 ± 6.3	8.84 ± 0.53	5000	0.2	128
170px	84g	CH2...methylcyclopropane	4.30 ± 0.87	1.30 ± 0.25	198 ± 9.6	0.3	46.0
180px	84h	CH2CH2CH2OH	5.39 ± 0.21	2.50 ± 0.20	217 ± 19	0.5	40.2
200px	84i	CH2CH2(OCH3)2	6.80 ± 1.10	1.69 ± 0.09	110 ± 7.7	0.2	16.2
180px	84j	CH2CO2CH3	11.9 ± 1.4	0.81 ± 0.10	29.1 ± 1.0	0.07	2.4
185px	84k	CH2CON(CH3)2	12.2 ± 3.8	6.40 ± 1.70	522 ± 145	0.5	42.8
200px	84l	CH2CH2CH2OMs	36.3 ± 2.1	17.3 ± 1.2	5000	0.5	138
170px	84m	COCH(CH3)2	2100 ± 140	102 ± 23	>10000	0.05	-
210px	84n	(CH2)2Pht	4.23 ± 0.48	0.84 ± 0.02	441 ± 66.0	0.2	104
210px	84o	(CH2)3Pht	9.10 ± 1.10	0.59 ± 0.07	74.0 ± 11.6	0.06	8.1
230px	84p	(CH2)4Pht	2.38 ± 0.22	0.21 ± 0.02	190 ± 18.0	0.09	79.8
230px	84q	(CH2)5Pht	2.40 ± 0.17	0.34 ± 0.03	60.0 ± 3.10	0.1	25.0
270px	84r	(CH2)8Pht	2.98 ± 0.30	0.20 ± 0.02	75.0 ± 3.6	0.07	25.2
170px	84sd	CH2CH=CH-CH3	15 ± 1	75 ± 5	400 ± 80	5.0	26.7
170px	84td	CH2C(Br)=CH2	30 ± 5	200 ± 40	>1000	6.7	-
170px	84ud	CH2CH=CH2I(E)	30 ± 5	960 ± 60	295 ± 33	32.0	9.8
170px	84vd	CH2C≡CH	14 ± 1	100 ± 30	>1000	7.1	-
170px	84wd	CH2C6H5	42 ± 12	100 ± 17	600 ± 100	2.4	14.3
170px	84xd	CH2C6H4-2-CH3	93 ± 19	225 ± 40	>1000	2.4	-
160px	85ad	para-H	113 ± 41	100 ± 20	>1000	0.9	-
170px	85bd	para-Cl, meta-Cl	29 ± 4	50 ± 6	500 ± 120	1.7	17.2
170px	85cd	para-Me	17 ± 7	500 ± 30	>1000	29.4	-
180px	85dd	para-CH(CH3)2	500 ± 120	450 ± 80	>1000	0.9	-
190px	85ed	para-n-C3H7	500 ± 100	300 ± 12	750 ± 160	0.6	1.5

• ^ɑIC₅₀ for displacement of [³H]cocaine. IC₅₀ for cocaine = 67.8 ± 8.7 (nM)
• ^bIC₅₀ values for displacement of [³H]WIN 35428
• ^cIC₅₀ values for displacement of [³H]citalopram
• ^dThe standard K_i value for the displacement of [³H]GBR 12935, [³H]paroxetine, and [³H]nisoxetine were 27 ± 2, 3 ± 0.2, and 80 ± 28 nM, respectively, for these experiments

3β-(4-alkylthiophenyl)nortropanes^[12]

Structure 150px	Compound	R1	R2	Inhibition of [3H]WIN 35,428 @ DAT IC50 (nM)	Inhibition of [3H]Paroxetine @ 5-HTT Ki (nM)	Inhibition of [3H]Nisoxetine @ NET Ki (nM)	NET/DAT (uptake ratio)	NET/5-HTT (uptake ratio)
See 7a—7h table
	7a	CH3	CH3	9 ± 3	0.7 ± 0.2	220 ± 10	24	314
	7b	C2H5	CH3	232 ± 34	4.5 ± 0.5	1170 ± 300	5	260
160px	8a	CH3	H	28 ± 6	0.19 ± 0.01	21 ± 6	0.8	110
170px	8b	C2H5	H	177 ± 62	1.26 ± 0.05	118 ± 13	0.7	94
210px	9a	CH3	FCH2CH2CH2	112 ± 2	3 ± 1	960 ± 100	9	320
215px	9b	C2H5	FCH2CH2CH2	1,200 ± 200	27 ± 2	>2,000	2	74
200px	10a	CH3	CH2=CH2CH2	71 ± 25	5.5 ± 0.8	2,000 ± 500	28	364
205px	10b	C2H5	CH2=CH2CH2	1,100 ± 100	47 ± 3	>2,000	2	43
200px	11a	CH3	CH3CH2CH2	74 ± 20	5.7 ± 0.6	1,200 ± 140	16	211
205px	11b	C2H5	CH3CH2CH2	900 ± 300	49 ± 6	>2,000	2	41

See: Bridged cocaine derivatives & N8 Tricyclic (2β—crossed-over) N8—to—3β replaced aryl linked (expansive front-bridged) cocaine analogues

U.S. Patent 6,150,376

Template:Sort-under

Activity at monoamine transporters: Binding Affinities & MAT Inhibition of Bridged Phenyltropanes K_i (nM)

Compound # (S. Singh's #)	2β=R	[3H]Mazindol binding	[3H]DA uptake	[3H]5-HT uptake	[3H]NE uptake	selectivity [3H]5-HT/[3H]DA
cocaine	CO2CH3	375 ± 68	423 ± 147	155 ± 40	83.3 ± 1.5	0.4
(–)-40 (–)-128		54.3 ± 10.2	60.3 ± 0.4	1.76 ± 0.23	5.24 ± 0.07	0.03
(+)-40 (+)-128		79 ± 19	114 ± 28	1.48 ± 0.07	4.62 ± 0.31	0.01
(±)-40 (±)-128		61.7 ± 8.5	60.3 ± 0.4	2.32 ± 0.23	2.69 ± 0.12	0.04
29β		620	1420	8030	—	—
30β		186	492	97.7	—	—
31β		47.0	211	28.5	—	—
29α		4140	20100	3920	—	—
30α		3960	8850	696	1150	—
45 129		6.86 ± 0.43	24.0 ± 1.3	1.77 ± 0.04	1.06 ± 0.03	0.07
42a 131a	n-Bu	4.00 ± 0.07	2.23 ± 0.12	14.0 ± 0.6	2.99 ± 0.17	6.3
41a 130a	n-Bu	17.2 ± 1.13	10.2 ± 1.4	78.9 ± 0.9	15.0 ± 0.4	7.8
42b 131b	Et	3.61 ± 0.43	11.3 ± 1.1	25.7 ± 4.3	4.43 ± 0.01	2.3
50a 133a	n-Bu	149 ± 6	149 ± 2	810 ± 80	51.7 ± 12	5.4
49a 132a	n-Bu	13.7 ± 0.8	14.2 ± 0.1	618 ± 87	3.84 ± 0.35	43.5
(–)-4		10500	16500	1890	70900	—
(+)-4		18500	27600	4630	38300	—
(–)-5		9740	9050	11900	4650	—
(+)-5		6770	10500	25100	4530	—
RTI-4229/Coc-242	N8/2β-C(O)CH(CO2Me)CH2N para-chloro	—	7.67 ± 0.31ɑ	226.54 ± 27.37b	510.1 ± 51.4c	—

• ^ɑValue for displacement of [³H]WIN 35,428 binding @ DAT
• ^bValue for displacement of [³H]paroxetine binding to SERT
• ^cValue for displacement of [³H]nisoxetine from NET

Fused tropane-derivatives as neurotransmitter reuptake inhibitors. Singh notes that all bridged derivatives tested displayed 2.5—104 fold higher DAT affinity than cocaine. The ones 2.8—190 fold more potent at DAT also had increased potency at the other two MAT sites (NET & SERT); NET having 1.6—78× increased activity. (+)-128 additionally exhibited 100× greater potency @ SERT, whereas 132a & 133a had 4–5.2× weaker 5-HTT (i.e. SERT) activity. Front-bridged (e.g. 128 & 129) had a better 5-HT/DA reuptake ratio in favor of SERT, while the back-bridged (e.g. 130–133) preferred placement with DAT interaction.^[1] U.S. Patent 5,998,405

Code	Compound	DA (μM)	NE (μM)	5-HT (μM)
1	(1 S,2S,4S,7R)-2-(3,4-Dichloro- phenyl)-8-azatricyclo[5.4.0.04,8]- undecan-11 -one O-methyl-oxime	0.012	0.0020	0.0033
2	(1 S,2S,4S,7R)-2-(3,4-Dichloro- phenyl)-8-azatricyclo[5.4.0.04,8]- undecan-11-one	0.18	0.035	0.0075
3	(1 S,3S,4S,8R)-3-(3,4-Dichloro-phenyl)-7-azatricyclo[5.3.0.04,8]- decan-5-one O-methyl-oxime	0.0160	0.0009	0.0032
4	(1 S,2S,4S,7R)-2-(3,4-Dichloro-phenyl)-8-azatricyclo[5.4.0.04,8]- undecan-11-ol	0.0750	0.0041	0.0028
5	(1 S,3S,4S,8R)-3-(3,4-Dichloro-phenyl)-7-azatricyclo[5.3.0.04,8]- decan-5-one	0.12	0.0052	0.0026
6	(1 S,3S,4S,8R)-3-(3,4-Dichloro- phenyl)-7-azatricyclo[5.3.0.04,8]-decan-5-ol	0.25	0.0074	0.0018
7	(1S,3S,4S,8R)-3- (3,4-Dichloro- phenyl)-7-azatricyclo[5.3.0.04,8]dec- 5-yl acetate	0.21	0.0061	0.0075
8	(1S,3S,4S,8R)-3-(3,4-Dichlorophenyl)-5-methoxy-7- azatricyclo[5.3.0.04,8]decane	0.022	0.0014	0.0001

1. 1-Chloroethyl chloroformate is used to remove N-methyl of trans-aryltropanes.
2. 2° amine is reacted with Br(CH₂)nCO₂Et.
3. Base used to abstract proton α- to CO₂Et group and complete the tricyclic ring closure step (Dieckmann cyclization).

To make a different type of analog (see Kozikowski patent above)

1. Remove N-Me
2. Add ɣ-bromo-chloropropane
3. Allow for cyclization with K₂CO₃ base and KI cat.

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(1R,2S,10R,12S)-15-methyl-15-azatetracyclo(10.2.1.0²,¹⁰.0⁴,⁹)pentadeca-4(9),5,7-trien-3-one^[3]

250px
Parent compound of a series of spirocyclic cocaine benzoyl linkage modification analogs created by Suzuki coupling method of ortho-substituted arylboronic acids and an enol-triflate derived from cocaine; which technically has the three methylene length of cocaine analogues as well as the single length which defines the phenyltropane series. Note that the carbomethoxyl group is (due to constraints in synthetic processes used in the creation of this compound) alpha configured; which is not the usual, most prevalent, conformation favored for the PT cocaine-receptor binding pocket of most such sub-type of chemicals. The above and below depictions show attested compounds synthesized, additionally with variations upon the Endo–exo isomerism of their structures.^[40]
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3-Phenyl-9-azabicyclo[3.3.1]nonane derivatives

To better elucidate the binding requirements at MAT, the methylene unit on the tropane was extended by one to create the azanonane analogs.^{[lower-alpha 9]} Which are the beginning of classes of modifications that start to become effected by the concerns & influences of macrocyclic stereocontrol.

Despite the loosened flexibility of the ring system, nitrogen constrained variants (such as were created to make the bridged class of phenyltropanes) which might better fit the rigid placement necessary to suit the spatial requirements needed in the binding pocket were not synthesized. Though front-bridged types were synthesized for the piperidine homologues: the trend of equal values for either isomers of that type followed the opposing trend of a smaller and lessened plasticity of the molecule to contend with a rationale for further constraining the pharmacophore within that scope. Instead such findings lend credence to the potential for the efficacy of fusing the nitrogen on an enlarged tropane, as like upon the compounds given below.

[3.3.1]azanonane analogues
displacement of bound [³H]WIN 35428^[1]

Structure	Compound # (S. Singh)	Ki (nM)
	Cocaine	32 ± 5 390 ± 220
	WIN 35065-2	33 ± 17 310 ± 220
	146a	4600 ± 510
	146b	5730 ± 570
	146c	3450 ± 310
	146d	3470 ± 350
	147	13900 ± 2010

3-Phenyl-7-azabicyclo[2.2.1]heptane derivatives

Ring-contracted analogs of phenyltropanes did not permit sufficient penetration of the phenyl into the target binding site on MAT for an affinity in the efficacious range. The distance from the nitrogen to the phenyl centroid for 155a was 4.2 and 155c was 5.0 Å, respectively. (Whereas troparil was 5.6 & compound 20a 5.5 angstroms). However piperidine homologues (discussed below) had comparable potencies.^{[lower-alpha 10]}

Azabornanes with longer substitutions at the 3β-position (benzoyloxys alkylphenyls, carbamoyls etc.) or with the nitrogen in the position it would be on the piperidine homologues (i.e. arrangements of differing locations for the nitrogens being either distal or proximal within the terms required to facilitate the framework of the compound to a correlative proportion, functional for the given moiety), were not synthesized, despite conclusions that the nitrogen to phenyl length was the issue at variance enough to be the interfering factor for the proper binding of the compressed topology of the azabornane. Carroll, however, has listed benzoyloxy azabornanes in patents.^[3]

[2.2.1]azabornane analogues
displacement of bound [³H]WIN 35428^[1]

Structure	Compound # (S. Singh)	Ki (nM)
	Cocaine	32 ± 5 390 ± 220
	WIN 35065-2	33 ± 17 310 ± 220
	155a	60,400 ± 4,800
	155b	96,500 ± 42
	155c	5,620 ± 390
	155d	18,900 ± 1,700

Piperidine homologues had comparable affinity & potency spreads to their respective phenyltropane analogues. Without as much of a discrepancy between the differing isomers of the piperidine class with respect to affinity and binding values as had in the phenyltropanes.

Phenyltropane 4-aryl-3-carboalkoxy-piperidine analogues^[1]

Structure	Compound # (S. Singh)	X = para- / 4′- Substitution	R = 2-tropane position	DAT (IC50 nM) [H3]WIN 35428 binding displacement	DA (IC50 nM) [H3]DA uptake	Selectivity Uptake/Binding
	Cocaine	H	CO2Me	102 ± 9	239 ± 1	2.3
	(±)-166a	Cl	β-CO2CH3	53.7 ± 1.9	37.8 ± 7.9	0.7
	(-)-166a	Cl	β-CO2CH3	24.8 ± 1.6	85.2 ± 2.6	3.4
	(+)-166a	Cl	β-CO2CH3	1360 ± 125	5090 ± 172	3.7
	(-)-167a	Cl	β-CO2OH	75.3 ± 6.2	49.0 ± 3.0	0.6
	(+)-167a	Cl	β-CO2OH	442 ± 32	—	—
	(-)-168a	Cl	β-CO2OAc	44.7 ± 10.5	62.9 ± 2.7	1.4
	(+)-168a	Cl	β-CO2OAc	928 ± 43	2023 ± 82	2.2
	(-)-169a[42]	Cl	β-n-Pr	3.0 ± 0.5	8.3 ± 0.6	2.8
	(-)-170a	H	β-CO2CH3	769 ± 19	—	—
	(±)-166b	Cl	α-CO2CH3	197 ± 8	—	—
	(+)-166b	Cl	α-CO2CH3	57.3 ± 8.1	34.6 ± 3.2	0.6
	(-)-166b	Cl	α-CO2CH3	653 ± 38	195 ± 8	0.3
	(+)-167b	Cl	α-CO2OH	240 ± 18	683 ± 47	2.8
	(+)-168b	Cl	α-CO2OAc	461 ± 11	—	—
	(+)-169b	Cl	α-n-Pr	17.2 ± 0.5	23.2 ± 2.2	1.3

Heterocyclic N-Desmethyl^[43]
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Activity @ MAT for piperidine homologues of phenyltropanes, including naphthyl derivatives^[44]

Structure	Compound #	[3 H]DA uptake (nM) IC50	[3 H]DA uptake (nM) Ki	[3 H]NE uptake (nM) IC50	[3 H]NE uptake (nM) Ki	[3 H]5-HTT uptake (nM) IC50	[3 H]5-HTT uptake (nM) Ki	Uptake Ratio DA/5-HT (Ki)	Uptake Ratio NE/5-HT (Ki)
	Cocaine	459 ± 159	423 ± 147	127 ± 4.1	108 ± 3.5	168 ± 0.4	155 ± 0.4	2.7	0.69
	Fluoxetine	>4500	>2500	193 ± 4.1	176 ± 3.5	8.1 ± 0.7	7.3 ± 0.7	624	24
	20	75 ± 9.1	69 ± 8.1	101 ± 3.3	88 ± 2.9	440 ± 30	391 ± 27	0.18	0.23
	6	23 ± 1.0	21 ± 0.9	-	34 ± 0.8	8.2 ± 0.3	7.6 ± 0.2	2.8	4.5
Error creating thumbnail: Unable to save thumbnail to destination	7	>1000	947 ± 135	-	241 ± 1.7	8.2 ± 0.3	7.6 ± 0.2	22.6	5.7
	8	94 ± 9.6	87 ± 8.9	-	27 ± 1.6	209 ± 17	192 ± 16	0.45	0.14
	9	293 ± 6.4	271 ± 5.9	-	38 ± 4.0	13 ± 0.7	12 ± 0.7	23	3.2
	19	97 ± 8.6	90 ± 8.0	34 ± 2.5	30 ± 2.3	3.9 ± 0.5	3.5 ± 0.5	26	8.6
	10	326 ± 1.2	304 ± 1.1	337 ± 37	281 ± 30	113 ± 4.3	101 ± 3.8	3.0	2.8
	14	144 ± 20	131 ± 18	204 ± 5.6	175 ± 4.8	155 ± 3.9	138 ± 3.5	0.95	1.3
	15	>1800	>1700	>1300	>1100	275 ± 39	255 ± 37	>6	>4
	16	>1000	964 ± 100	>1200	>1000	334 ± 48	309 ± 44	3.1	3.5
	17	213 ± 30	187 ± 26	399 ± 12	364 ± 9.2	189 ± 37	175 ± 34	1.1	2.1
	18	184 ± 30	173 ± 26	239 ± 42	203 ± 36	67 ± 4.5	62 ± 4.1	2.8	3.3

Source:^[3]

x155pxx155pxx155px
cf. Fencamfamine

Code	SERT Ki (nM)	NET Ki (nM)	DAT Ki (nM)	Radiolabel	In vivo study	Refs.
1	0.2	102.2	29.9	11C	Non-human primate	[46]
2	0.2	31.7	32.6	11C	Non-human primate	[47]
3	0.05	24	3.47	123I	Rat	[48]
4	0.08	28	13	18F	Non-human primate	[49]
5	0.11	450	22	11C	Rat, monkey	[50]

• 
  IPT (N-3-iodoprop-(2E)-ene-2β-carbomethoxy-3β-(4′-chlorophenyl)tropane), can be radiolabeled with ¹²³I or ¹²⁵I and used as a ligand to map several MATs
• 
  N-4-Fluorobut-2-yn-1-yl-2β-carbomethoxy-3β-phenyltropane (PR04.MZ) often radiolabeled.^[51][52]
• 
  JHC1-64.^[53] A fluorescent analog, similar in its long chain off of the nitrogen bridge similar to the transition metal phenyltropane types.

These compounds include transition metals in their heteroatomic conformation, unlike non-radiolabel intended chelates where their element is chosen for intrinsic affectation to binding and function, these are tagged on by a "tail" (or similar) with a sufficient spacer to remain separated from known binding properties and instead are meant to add radioactivity enough to be easily tracked via observation methods that utilize radioactivity. As for anomalies of binding within the spectrum of the under-written kinds just mentioned: other factors not otherwise considered to account for its relatively lower potency, "compound 89c" is posited to protrude forward at the aryl place on its moiety toward the MAT ligand acceptor site in a manner detrimental to its efficacy. That is considered due to the steric bulk of the eight-position "tail" chelate substituted constituent, overreaching the means by which it was intended to be isolated from binding factors upon a tail, and ultimately nonetheless, interfering with its ability to bind. However, to broach this discrepancy, decreasing of the nitrogen tether at the eight position by a single methylene unit (89d) was shown to bring the potency of the analogous compound to the expected, substantially higher, potency: The N-methyl analog of 89c having an IC₅₀ of 1.09 ± 0.02 @ DAT & 2.47 ± 0.14 nM @ SERT; making 89c upwards of thirty-three times weaker at those MAT uptake sites.^{[lower-alpha 11]}

"Transition metal" chelated phenyltropanes^[1]

Structure	Compound # (S. Singh)	X = para- / 4′- Substitution	Configuration	DAT (IC50 nM) displacement of [H3]WIN 35428	5-HTT (IC50 nM) [H3]Citalopram	Selectivity 5-HTT/DAT
	WIN 35428	F	-	11.0 ± 1.0	160 ± 20	14.5
+2β-chelated phenyltropanes
	73 TRODAT-1ɑ	Cl	-	R=13.9, S=8.42b	-	-
	74 TROTEC-1	F	-	high affinity site = 0.15 ± 0.04c low affinity site = 20.3 ± 16.1c	-	-
N-chelated phenyltropanes
	89a	F	2β	5.99 ± 0.81	124 ± 17	20.7
	89b	F	2α	2960 ± 157	5020 ± 1880	1.7
	89c	3,4-Cl2	2β	37.2 ± 3.4	264 ± 16	7.1
	89d	Cl	-	0.31 ± 0.03d	-	-

• ^ɑIUPAC: [2-[[2-[[[3-(4-chlorophenyl)-7-methyl-8-azabicyclo[3,2,1]oct-2-yl]methyl]-(2-mercaptoethyl)amino]ethyl]amino]ethanethiolato-(3—)-N2, N2′, S2, S2′]oxo-[1''R''-(''exo'', ''exo'')]-[99mTc]technetium
• ^bR- & S- isomer values are K_i (nM) for displacement of [¹²⁵I]IPT with technetium-99m replaced by rhenium
• ^cIC₅₀ (nM) values for displacement of [³H]WIN 35428 with ligand tricarbonyltechnetium replaced with rhenium. (IC₅₀ for WIN 35428 were 2.62 ± 1.06 @ high affinity binding & 139 ± 72 @ low affinity binding sites)
• ^dK_i value for displacement of [¹²⁵I]IPT radioligand.

Phenyltropanes can be grouped by "N substitution" "Stereochemistry" "2-substitution" & by the nature of the 3-phenyl group substituent X.
Often this has dramatic effects on selectivity, potency, and duration, also toxicity, since phenyltropanes are highly versatile. For more examples of interesting phenyltropanes, see some of the more recent patents, e.g. U.S. Patent 6,329,520, U.S. Patent 7,011,813, U.S. Patent 6,531,483, and U.S. Patent 7,291,737.

Potency in vitro should not be confused with the actual dosage, as pharmacokinetic factors can have a dramatic influence on what proportion of an administered dose actually gets to the target binding sites in the brain, and so a drug that is very potent at binding to the target may nevertheless have only moderate potency in vivo. For example, RTI-336 requires a higher dosage than cocaine. Accordingly, the active dosage of RTI-386 is exceedingly poor despite the relatively high ex vivo DAT binding affinity.

Many molecular drug structures have exceedingly similar pharmarcology to phenyltropanes, yet by certain technicalities do not fit the phenyltropane moniker. These are namely classes of dopaminergic cocaine analogues that are in the piperidine class (a category that includes methylphenidate) or benztropine class (such as Difluoropine: which is extremely close to fitting the criteria of being a phenyltropane.) Whereas other potent DRIs are far removed from being in the phenyltropane structural family, such as Benocyclidine or Vanoxerine.

Most any variant with a tropane locant—3-β (or α) connecting linkage differing from, e.g. longer than, a single methylene unit (i.e. "phenyl"), including alkylphenyls (see the styrene analog, first image given in example below) is more correctly a "cocaine analogue" proper, and not a phenyltropane. Especially if this linkage imparts a sodium channel blocker functionality to the molecule.

• List of cocaine analogues
  • List of local anesthetics
• List of methylphenidate analogues

• U.S. Provisional Patent Application listing examples of compounds that are tropanes for prospective use in research
• Article on cocaine analogue research

Template:Chemical classes of psychoactive drugs

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