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Substituted piperazine

Topic: Chemistry

 From HandWiki - Reading time: 7 min

Short description: Class of chemical compounds

Substituted piperazines are a class of chemical compounds based on a piperazine core.[1] Some are used as recreational drugs and some are used in scientific research.[2]

List of substituted piperazines

Benzylpiperazines

Chemical structures of selected benzylpiperazines
  • 1-Benzylpiperazine (BZP)
    1-Benzylpiperazine (BZP)
  • 1-Methyl-4-benzylpiperazine (MBZP)
    1-Methyl-4-benzylpiperazine (MBZP)
  • 1,4-Dibenzylpiperazine (DBZP)
    1,4-Dibenzylpiperazine (DBZP)
  • 3,4-Methylenedioxy-1-benzylpiperazine (MDBZP)
    3,4-Methylenedioxy-1-benzylpiperazine (MDBZP)
  • 4-Bromo-2,5-dimethoxy-1-benzylpiperazine (2C-B-BZP)
    4-Bromo-2,5-dimethoxy-1-benzylpiperazine (2C-B-BZP)
  • Methoxypiperamide (MeOP, MEXP) ((4-methoxyphenyl)(4-methylpiperazin-1-yl)methanone)
    Methoxypiperamide (MeOP, MEXP) ((4-methoxyphenyl)(4-methylpiperazin-1-yl)methanone)
  • Sunifiram (1-benzoyl-4-propanoylpiperazine)
    Sunifiram (1-benzoyl-4-propanoylpiperazine)
  • 3-Methylbenzylpiperazine (3-MeBZP)
    3-Methylbenzylpiperazine (3-MeBZP)
  • Befuraline (also produces benzylpiperazine as a metabolite)
    Befuraline
    (also produces benzylpiperazine as a metabolite)
  • Fipexide (also produces substituted benzylpiperazine as a metabolite)
    Fipexide
    (also produces substituted benzylpiperazine as a metabolite)
  • Piberaline (also produces benzylpiperazine as a metabolite)
    Piberaline
    (also produces benzylpiperazine as a metabolite)

Phenylpiperazines

See also: Chemistry:Phenylpiperazine

ortho-Substituted

  • 2-Chlorophenylpiperazine (oCPP)
  • 2-Methylphenylpiperazine (oMPP)
  • 2-Methoxyphenylpiperazine (oMeOPP)
  • Mefeclorazine
  • Vortioxetine

Enpiprazole is known to produce oCPP as a metabolite. It was initially anticipated to produce oMeOPP as a metabolite, but this proved not to be the case.

meta-Substituted

Trazodone, nefazodone, etoperidone, mepiprazole, and others produce mCPP as a metabolite.[3]

para-Substituted

  • 4-Chlorophenylpiperazine (pCPP)
  • 4-Fluorophenylpiperazine (pFPP)
  • 4-Methylphenylpiperazine (pMPP)
  • 4-Methoxyphenylpiperazine (pMeOPP, MeOPP)
  • 4-Nitrophenylpiperazine (pNPP; PAL-175) – selective partial serotonin releasing agent[4]
  • 4-Trifluoromethylphenylpiperazine (pTFMPP)

Multiple substitutions

  • 2,3-Dichlorophenylpiperazine (2,3-DCPP)
  • 3,4-Dichlorophenylpiperazine (3,4-DCPP)
  • 2,3-Dimethylphenylpiperazine (DMPP)
  • 3-Trifluoromethyl-4-chlorophenylpiperazine (TFMCPP; PAL-179) – selective partial serotonin releasing agent[4]

Others

  • 1-Phenylpiperazine (PP)

Other arylpiperazines

  • 1-(1-Naphthyl)piperazine (1-NP)
  • 1-(2-Pyrimidinyl)piperazine (1-PP)
  • ORG-12962 (1-(5-trifluoromethyl-6-chloropyridin-2-yl)piperazine)
  • Quipazine (2-piperazin-1-ylquinoline)

Many azapirones such as buspirone, gepirone, and tandospirone produce 1-PP as a metabolite.

By drug class

Antianginals

Antidepressants

Antihistamines

Antiserotonergics

Antipsychotics

Recreational Drugs

  • 4-Bromo-2,5-dimethoxy-1-benzylpiperazine (2C-B-BZP)
  • 1-Benzylpiperazine (BZP)
  • 2,3-Dichlorophenylpiperazine (DCPP)
  • 1,4-Dibenzylpiperazine (DBZP)
  • 4-Methyl-1-benzylpiperazine (MBZP)
  • 3-Chlorophenylpiperazine (mCPP)
  • 3,4-Methylenedioxy-1-benzylpiperazine (MDBZP)
  • 4-Methoxyphenylpiperazine (MeOPP)
  • Methoxypiperamide (MeOP or MEXP)
  • 4-Chlorophenylpiperazine (pCPP)
  • 4-Fluorophenylpiperazine (pFPP)
  • 3-Trifluoromethylphenylpiperazine (TFMPP)

Urologicals

Others

Activities

Template:Sticky

Monoamine release (EC50, nM) of arylpiperazines
Compound PAL # Serotonin Norepinephrine Dopamine Type Ref
1-Benzylpiperazine (BZP) ND 6050–>100000 62.2–68 175–600 NDRA [5][6][7][8][9][10]
1-Phenylpiperazine (PP) ND 880 186 2530 SNRA [11]
2-Me-PP (oMPP) PAL-169 175 39.1 296–542 SNDRA [11][12][10]
2-OMe-PP (oMeOPP) ND ND ND ND ND ND
2-TFM-PP (oTFMPP) ND 570 350 11200 SNRA [11]
2-SMe-PP (oMTPP) ND 270 >10000 >10000 SRA [11]
2-Et-PP (oEtPP) ND 290 830 >10000 SNRA [11]
2-Chloro-PP (oCPP) ND 310 26 >3000 NRA [11]
2-Bromo-PP (oBPP) ND 132 33 250 SNDRA [11]
2-Nitro-PP (oNPP) ND 1870 770 >10000 SNRA [11]
3-Chloro-PP (mCPP) ND 28–39 1400–>10000 >10000–63000 SRA [6][13][14][15]
3-Fluoro-PP (mFPP) ND 115 340 2400 SNRA [11]
3-Me-PP (mMPP) ND 110 >20000 >20000 SRA [11]
3-OMe-PP (mMeOPP) ND 650 >10000 >10000 SRA [11]
3-OH-PP (mOHPP) ND 230 174 2500 SNRA [11]
3-TFM-PP (TFMPP) ND 121 >10000 >10000 SRA [8][7][9]
4-Chloro-PP (pCPP) ND ND ND ND ND ND
4-Fluoro-PP (pFPP) ND 230 3200 >10000 SRA [11]
4-Me-PP (pMPP) PAL-233 220 >10000 >20000 SRA [11][10]
4-OMe-PP (pMeOPP) ND 3200 440–1500 6300–11000 SNDRA [11][6]
4-TFM-PP (pTFMPP) ND ND ND ND ND ND
4-Ac-PP (pAcPP) ND 50 150 3000 SNRA [11]
4-CN-PP (pCNPP) ND 36 6300 >10000 SRA [11]
4-Phenyl-PP (pPhPP) ND >10000 1520 5200 NDRA [11]
4-OH-PP (pOHPP) ND >10000 230 850 NDRA [11]
4-Nitro-PP (pNPP) PAL-175 19–43 >10000 >10000 SRA [11][4]
2,3-Dichloro-PP (2,3-DCPP) ND 10 36 108 SNDRA [11]
2,3-DiMe-PP (2,3-DMPP) PAL-218 24–26 13.7–56 1207–1320 SNRA [11][4][10]
2,4-Difluoro-PP (2,4-DFPP) ND 470 2300 >10000 SNRA [11]
3,4-Dichloro-PP (3,4-DCPP) ND ND ND ND ND ND
3,4-Difluoro-PP (3,4-DFPP) ND 76 9200 >10000 SRA [11]
3-TFM-4-Cl-PP (TFMCPP) PAL-179 33 >10000 >10000 SRA [4]
Notes: Assays were done using rat brain synaptosomes.

See also

References

  1. ↑ Laras, Y.; Garino, C.; Dessolin, J.; Weck, C.; Moret, V.; Rolland, A.; Kraus, J.-L. (2009-02-01). "New N4-substituted piperazine naphthamide derivatives as BACE-1 inhibitors". Journal of Enzyme Inhibition and Medicinal Chemistry 24 (1): 181–187. doi:10.1080/14756360802048939. ISSN 1475-6366. PMID 18770069. https://doi.org/10.1080/14756360802048939. 
  2. ↑ Alghamdi, Saad; Alshehri, Mohammed M.; Asif, Mohammad (2022). "The Neuropharmacological Potential of Piperazine Derivatives: A Mini- Review" (in en). Mini-Reviews in Organic Chemistry 19 (7): 798–810. doi:10.2174/1570193x19666220119120211. https://www.eurekaselect.com/article/120285. 
  3. ↑ "Metabolism of m-CPP, trazodone, nefazodone, and etoperidone: clinical and forensic aspects". Drug Metab Rev 57 (2): 115–146. February 2025. doi:10.1080/03602532.2025.2465482. PMID 39945551. 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 "Studies of the biogenic amine transporters. 14. Identification of low-efficacy "partial" substrates for the biogenic amine transporters". J Pharmacol Exp Ther 341 (1): 251–262. April 2012. doi:10.1124/jpet.111.188946. PMID 22271821. 
  5. ↑ "Therapeutic potential of monoamine transporter substrates". Curr Top Med Chem 6 (17): 1845–1859. 2006. doi:10.2174/156802606778249766. PMID 17017961. 
  6. ↑ 6.0 6.1 6.2 "The effects of non-medically used psychoactive drugs on monoamine neurotransmission in rat brain". Eur J Pharmacol 559 (2–3): 132–137. March 2007. doi:10.1016/j.ejphar.2006.11.075. PMID 17223101. https://citeseerx.ist.psu.edu/document?repid=rep1&type=pdf&doi=00665d67c36dcf1777989b70cc901c654420a0c7. 
  7. ↑ 7.0 7.1 "Effects of "Legal X" piperazine analogs on dopamine and serotonin release in rat brain". Ann N Y Acad Sci 1025: 189–197. October 2004. doi:10.1196/annals.1316.024. PMID 15542717. Bibcode: 2004NYASA1025..189B. 
  8. ↑ 8.0 8.1 "N-substituted piperazines abused by humans mimic the molecular mechanism of 3,4-methylenedioxymethamphetamine (MDMA, or 'Ecstasy')". Neuropsychopharmacology 30 (3): 550–560. March 2005. doi:10.1038/sj.npp.1300585. PMID 15496938. 
  9. ↑ 9.0 9.1 "Dopamine-releasing agents". Dopamine Transporters: Chemistry, Biology and Pharmacology. Hoboken [NJ]: Wiley. July 2008. pp. 305–320. ISBN 978-0-470-11790-3. OCLC 181862653. https://bitnest.netfirms.com/external/Books/Dopamine-releasing-agents_c11.pdf. 
  10. ↑ 10.0 10.1 10.2 10.3 "Behavioral, biological, and chemical perspectives on atypical agents targeting the dopamine transporter". Drug Alcohol Depend 147: 1–19. February 2015. doi:10.1016/j.drugalcdep.2014.12.005. PMID 25548026. 
  11. ↑ 11.00 11.01 11.02 11.03 11.04 11.05 11.06 11.07 11.08 11.09 11.10 11.11 11.12 11.13 11.14 11.15 11.16 11.17 11.18 11.19 11.20 11.21 11.22 11.23 "Binding of the amphetamine-like 1-phenyl-piperazine to monoamine transporters". ACS Chem Neurosci 3 (9): 693–705. September 2012. doi:10.1021/cn300040f. PMID 23019496. 
  12. ↑ "Cocaine-like discriminative stimulus effects of "norepinephrine-preferring" monoamine releasers: time course and interaction studies in rhesus monkeys". Psychopharmacology (Berl) 234 (23–24): 3455–3465. December 2017. doi:10.1007/s00213-017-4731-5. PMID 28889212. 
  13. ↑ "Therapeutic and adverse actions of serotonin transporter substrates". Pharmacol Ther 95 (1): 73–88. July 2002. doi:10.1016/s0163-7258(02)00234-6. PMID 12163129. 
  14. ↑ "Serotonin releasing agents. Neurochemical, therapeutic and adverse effects". Pharmacol Biochem Behav 71 (4): 825–836. April 2002. doi:10.1016/s0091-3057(01)00669-4. PMID 11888573. 
  15. ↑ "Evidence for noncompetitive modulation of substrate-induced serotonin release". Synapse 64 (11): 862–869. November 2010. doi:10.1002/syn.20804. PMID 20842720. 

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