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Nicotinic agonist

Topic: Chemistry

 From HandWiki - Reading time: 20 min

Short description: Drug that binds to and activates nicotinic acetylcholine receptors

A nicotinic agonist is a drug that mimics the action of acetylcholine (ACh) at nicotinic acetylcholine receptors (nAChRs). The nAChR is named for its affinity for nicotine.

Examples include nicotine (by definition), acetylcholine (the endogenous agonist of nAChRs), choline, epibatidine, lobeline, varenicline and cytisine.[1]

History

Chemical structure of ABT-418

Nicotine has been known for centuries for its intoxicating effect. It was first isolated in 1828 from the tobacco plant by German chemists Posselt and Reimann.[2]

The discovery of positive effects from nicotine on animal memory was discovered by in vivo studies in the mid 1980s. That research led to a new era in studies of nicotinic acetylcholine receptors (nAChR) and their stimulation but until then the focus had mainly been on nicotine addiction.[3][4] The development of nAChR agonists began in the early 1990s after the discovery of nicotine's positive effects. Some research showed a possible therapy option in preclinical studies. ABT-418 was one of the first in a series of nAChR agonists and it was designed by Abbott Labs.[4] ABT-418 showed significant increase of delayed matching-to-sample (DMTS) performance in matured macaque apes of different species and sex.[5] ABT-418 has also been examined as a possible treatment to Alzheimer's disease, Parkinson's disease and attention-deficit hyperactivity disorder: those experiments showed positive outcomes.[4]

One of the first nAChR active compounds, besides nicotine, that was marketed as a drug was galantamine, a plant alkaloid that works as a weak cholinesterase inhibitor (IC50 = 5 μM) as well as an allosteric sensitizer for nAChRs (EC50=50 nM).[6]

Nicotinic acetylcholine receptors and their signaling system

Nicotinic acetylcholine receptor classification

Signaling system

In the human nervous system nicotinic cholinergic signals are extended throughout the system, where the neurotransmitter acetylcholine (ACh) plays a key role in activating ligand-gated ion channels.[7] The cholinergic system is a vital nervous pathway, where cholinergic neurons synthesize, store and release the neurotransmitter ACh. The main receptors that convert the ACh messages are the cholinergic muscarinic acetylcholine receptors, neuronal and muscular nAChRs. When looking back at evolutionary history, ACh is considered to be the oldest transmitter molecule and became present before the nervous cell. In the nervous system cholinergic stimulation mediated through nAChRs controls pathways such as release of transmitters and cell sensitivity, which can influence physiological activity including sleep, anxiety, processing of pain and cognitive functions.[8]

Nicotinic acetylcholine receptors

nAChRs are cholinergic receptors found in the central nervous system (CNS), peripheral nervous systems (PNS) and skeletal muscles, these receptors are ligand-gated ion channels with binding sites for acetylcholine and other molecules. When ACh or other agonists bind to the receptors it stabilizes the open state of the ion channel allowing influx of cations such as potassium, calcium and sodium ions. The nAChRs are made up by different subunits which determine the quaternary structure of the receptor, those subunits are α subunits (α1−α10), β subunits (β1−β4), one δ subunits, one γ subunit and one ε subunit. nAChRs can be either heteromeric or homomeric. The heteromeric receptors found in the central nervous system are made up by two α subunits and three β subunits with the binding site at the interface of α and the adjacent subunit. These receptors contain two binding sites per receptor and have different affinity for chemicals based on the composition of subunits. Both binding sites work together and thus, both sites need to be occupied with a nAChR agonist so that channel activation can take place.[9] nAChRs containing α2−α6 and β2−β4 subunits have been shown to have higher affinity for ACh than other receptors. Homomeric receptors contain 5 identical subunits, they have 5 binding sites located at the interface between two adjacent subunits. In the year 2000 two homomeric receptors had been identified in humans, the α7 and α8 receptors.[8][10][11]Cite error: Closing </ref> missing for <ref> tag[12]

α7 receptor agonists

α7 receptors are homomeric neuronal acetylcholine receptors consisting of five α7 subunits and has five ACh binding sites. Abnormality in the α7 receptors expression have been reported to influence progression of diseases such as Alzheimer's disease and schizophrenia. The α7 are not believed to have as much affinity for nicotine as the heteromeric receptor but instead they have shown more affinity for alpha bungarotoxin which is a nicotinic antagonist found in venom of some snakes. Targeting of α7 receptors is therefore thought to be useful in treatment of Alzheimer's disease and schizophrenia.[9][13]

Muscle type receptor agonists

nAChR are found in the neuromuscular junction on skeletal muscles. Two different receptors have been found, one of which has primarily been found in adults contains two α1 subunits, one β1, one ε and one δ, the other one has been found in fetuses and contains γ subunit instead of the ε subunit. The nAChRs take part in the depolarization of the muscular endplate by increasing cation permeability leading to contraction of skeletal muscles.[14] The nAChRs found in the skeletal muscle system have two ACh binding sites, one of which is found at the interface between α1 and δ subunits while the other one is found at the interface between α1 and γ or ε subunits. Among nAChR antagonists designed specifically for the neuromuscular system are nerve gases and other poisons designed to quickly kill humans or other animals and insects.[15]

Binding

ACh binds to nAChR because of charge difference between the molecule and the surface of the receptor. When binding to nAChR ACh fits into a binding pocket shaped by loops A, B and C which belong to α subunit and the adjacent subunit. When ACh is fitted into the binding pocket the loops of the nAChR undergo movement that leads to a coordination of the ACh molecule in the pocket enhancing the chemical bonds between the molecule and the receptor. After movement of the loops that belong to α subunit it's sometimes possible for the ACh molecule to form a bond, e.g. salt bridge, to the adjacent subunit enhancing the bonds between the receptor and ACh even further.[16]

Drug design

Drugs which influence nAChRs are typically agonists, partial agonists or antagonists.[1] However, some nAChR agonists - such as nicotine - act as depolarizing agents in a time-dependent manner (seconds or minutes) relative to concentration and nAChR subtype. Chronic exposure to some agonists can lead to long-lasting functional deactivation resulting from rapid and persistent desensitization. Partial nAChR agonists have been investigated as potential smoking cessation agents; believed to bind to nAChRs and stimulate the release of dopamine in smaller doses than that achieved by full agonists, and in the absence of nicotine.[17]

The lack of specificity among some nicotinic agonists - or nonspecific agonists - is well documented as a conflating factor for treating illnesses which require selectivity for specific nAChR subtypes. Many nonspecific agonists - such as ACh, nicotine and epibatidine - have been shown to target more than one subtype.[18][19]

Pharmacophore

Chemical structure of nicotine

The development of pharmacophore, an nAChR agonist, in 1970 suggested its receptor-binding activity depended on the presence of a positively charged nitrogen atom and hydrogen-bonding capacity conferred by either a carbonyl or nitro group - i.e., the carbonyl oxygen in acetylcholine or nitrogen in (S)-nicotine. Recent investigations have elucidated the structural and Stereochemical elements responsible for the binding capacity and potency of pharmacophore; the presence of a cationic centre and electronegative atoms able to form hydrogen bonds with the center of the pyridine ring in (S)-nicotine confer greater binding affinity, while the (S)-enantiomer is 10-100 times more potent than its (R) conformer.

The azabicyclic ring of epibatidine also affords favorable steric interactions with nAChR receptor, due to its specific internitrogen distance, N+-N, which has been proposed as a significant factor for agonist affinity, however, some debate remains as to its influence. Contemporary theories suggest a 7-8 Å difference between points complementing the protonated nitrogen atom and hydrogen-bond acceptor could enhance potency. Low electronic density near the protonated nitrogen and higher electron density toward the pyridine ring is favourable in protonated nicotine ligands containing pyridine ring.

Recent research has focussed on the α7 and α4β2 receptor subtypes for the development of drugs to treat nicotine dependence and cognitive impairment, such as Alzheimer's disease.[20]

Structure-activity relationships

Structure-activity relationships: Muscle nAChR agonists

Various models have been used to test the affinity of nAChR agonists for receptor subtypes by identifying the molecules and their structures - i.e., constituent groups and steric conformation - which confer greater affinity. By using a model for the nAChR muscle receptor subtype (α1)2β1δγ, the following results were obtained:

anatoxin > epibatidine > acetylcholine > DMPP >> cytisine > pyrantel > nicotine > coniine > tubocurare > lobeline,

where anatoxin had the highest activity efficacy, and tubocurare the lowest. In contrast, Acetylcholine induced a much longer opening time of the receptor, however, anatoxin proved more potent. These results suggest anatoxin derivatives could be improve understanding of structure-activity relationships (SAR) for muscle nAChRs.[21]

Succinylcholine chloride, which is a drug that's already on the market, is a bischoline ester and a short acting muscle relaxant. Bischoline esters are compounds that can act as a competitive agonist on muscle type nAChRs and have been used in SAR studies. In a Torpedo (α1)2β1δγ nAChR model it was demonstrated that the potency of bischoline ester agonists is dependent on the chain length as potency increases with longer chains. Efficacy seems to be independent of chain length since the highest efficacy is seen in bischoline esters with four to seven CH2 units and is lower for both fewer CH2 units and more.[22]

Structure-activity relationships: α4β2 nAChR agonists

Pyridin cyclopropan derivatives

Combining the structural elements of ACh and nicotine, thus reducing conformational flexibility with a cyclopropane ring, has led to the discovery of potent and selective α4β2 nAChR ligands. Modulation of three structural elements - the linker, and substitution of either the amino group or pyridine ring - can be used to determine the influence of ligands on potency and selectivity.

Factors which inhibit binding include steric hindrance within the amino group and/or saturated/unsaturated carbon-chain linkers - hence the preference for short-chained ether linkers. Increased binding affinity is often achieved if the pyridine ring is either mono- or di-substituted with halogens. Substitution on the amino group with three different amides increased binding; where methylamide had the greatest, other substituted amides showed a decrease in binding affinity due to steric hindrance and/or absence of a methyl group resulting in the loss of hydrophobic interactivity. The stereochemistry of pyridine nitrogen and/or the pyridine ring, qua stereoelectronic effects, show positive, albeit subtle effects on binding to α4β2 nAChR. A pyridyl ether ligand with a bromo-substituted pyridine, and metylatedamide-subtituted amino group exhibited the highest potency.[23]

Structure-activity relationships: α7 nAChR agonists

SEN12333/WAY-317538
Structure activity relationship model for α7 agonists

The search for selective and potent α7 nAChR agonists has produced a number of potential drug candidates; i.e., SEN12333/WAY-317538, and other compounds with desirable pharmacokinetic profiles, for which structure-activity relationships have been proposed, show selectivity for α7 nAChRs (versus α1, α3 and α4β2 nAChRs).[13]

The optimal pharmacophore of α7 nAChR agonist comprises a basic moiety attached via a carbon chain linked via an amide bridge to an aromatic moiety. The amide bridge can be inverted without affecting the potency of the agonist. Biaryl groups show more potency than monoaryl groups due to the presence of and aromatic moiety and biaryl aryl group substitution at position 2; potency is higher for agonists with an H+ donor/acceptor on the biaryl aryl group. Higher numbers of hydrogen bond acceptors likely decrease permeability across the blood–brain barrier (BBB) due to the polar surface area, and need to be taken into account when designing agonists targeting α7 nAChRs.[13]

Various cyclic amine groups - for example aryl piperazine, piperidine and morpholine - can be used as the basic moiety, while having limited affect on agonist potency. Acyclic tertiary amines are well sufficient as basic moieties, however larger groups negatively affect tolerability due to their sterics.[13]

Many derivatives of quinuclidine - such as quinuclidine amide - are known to be α7 nAChR agonists. SAR studies for quinuclidine amide have identified factors affecting potency and affinity of these agonists. Para-substitution of the quinuclidine ring, and a 3-(R) stereochemical configuration are favored. Enhanced activity is observed when a 5 membered ring is fused to aromatic moiety. Further enhancement can be achieved if the fused ring supplies electron resonance to the amide carbonyl, whereas activity is diminished if the ring contains hydrogen-bond donors.

The rigidity of quinuclidine and orthogonality of the nitrogen bridge relative to the amide carbonyl has been proposed as important for optimal binding. The stability of quinuclidine amide - a more potent derivative - in rat in vitro models were low, however, the addition of a methyl group to position 2 on the quinuclidine ring significantly increased its stability.[24]

Drug development

The development of nicotinic acetylcholine receptor agonists began in the early 1990s after the discovery of nicotine's positive effects on animal memory.[3][4] The development of nicotinic acetylcholine receptor agonists has come a long way since then. Nicotinic acetylcholine receptor agonists are gaining increasing attention as drug candidates for multiple central nervous system disorders such as Alzheimer's disease, schizophrenia, attention-deficit hyperactivity disorder (ADHD) and nicotine addiction.[25][26] Nicotinic acetylcholine receptors are receptors found in the central nervous system, the peripheral nervous systems and skeletal muscles. They are ligand-gated ion channels with binding sites for acetylcholine as well as other agonists. When agonists bind to a receptor it stabilizes the open state of the ion channel allowing influx of cations.[9]

In 2009 there were at least five drugs on the market that affect the nicotinic acetylcholine receptors.

Quinuclidine derivatives
200x200px 200x200px 200x200px
Quinuclidine carbamates Quinuclidine amides Quinuclidine ethers

Nicotine Agonist Drug

Active ingredient Product name Chemical name Pharmaceutical form Pharmacodynamic properties Therapeutic use Structure
Varenicline tartrate Champix, Chantix 7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino[2,3-h][3]benzazepine[26] Film coated tablet Partial agonist of the nicotinic acetylcholine receptor, subtype α4β2[27] Treatment of tobacco dependence[27] 150px
Galantamine hydrobromide Reminyl, Nivalin, Razadyne and Razadyn ER 4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]-benzazepin-6-ol[28] Sustained release capsule, film coated tablet, oral solution Cholinesterase inhibitor and a noncompetitive agonist of the nicotinic acetylcholine receptor[4] Treatment of dementia caused by Alzheimer's disease[29] 150px
Nicotine Nicorette, Nicotinell, Niquitin, Boots NicAssist, Commit, Habitrol, Nicoderm CQ, Nicotrol, Thrive 3-[(2S)-1-methylpyrrolidine-2-yl]pyridine Transdermal patch, gum, inhaler, nasal spray, lozenge, microtab, and is naturally found in tobacco Agonist of the nicotinic receptor,[30] both Ganglion type and α4β2[31] Treatment of tobacco dependence[32] 120px
Carbachol Miostat 2-[(aminocarbonyl)oxy]-N,N,N-trimethylethanaminium Intraocular solution Cholinergic agonist[33] Treatment of glaucoma 150px
Suxamethonium chloride (Succinylcholine chloride) Anectine, Quelicin Suxamethonium Chloride 2,2'-[(1,4-dioxobutane-1,4-diyl)bis(oxy)]bis(N,N,N-trimethylethanaminium) Intravenous or intramuscular injection Depolarizing neuromuscular blocking agent[34] Short acting muscle relaxant[35] 170px
Epibatidine Not listed 2-(6-chloropyridin-3-yl)-7-azabicyclo[2.2.1]heptane Not listed Agonist of the nicotinic acetylcholine receptor[36] Not used as a drug 150px

Other nicotinic agonists, albeit generally with limited clinical use, include:

  • lobeline, an agonist on Ganglion type nicotinic receptors and also affects sensory nerve terminals[31]
  • epibatidine, an agonist on Ganglion type, α4β2 and α7 receptors[31]
  • decamethonium causes depolarization block on muscle type receptors, similarly to suxamethonium[31]

Nicotinic versus muscarinic activity

Comparison of cholinergic agonists[37]
Substance Receptor specificity Hydrolysis by
acetylcholinesterase		 Comments
Muscarinic Nicotinic
Choline +++ +++ ++ Essential nutrient
Acetylcholine +++ +++ +++ Endogenous ligand
Carbachol ++ +++ - Used in the treatment of glaucoma
Methacholine +++ + ++
Bethanechol +++ - - Used in bladder and
gastrointestinal hypotonia.
Muscarine +++ - - Natural alkaloid found in certain mushrooms. Cause of mushroom poisoning
Nicotine - +++ - Natural alkaloid found in the tobacco plant.
Pilocarpine ++ - - Used in glaucoma
Oxotremorine ++ - -

Current status

Currently nicotine receptor agonist research and drug designing is aimed for treatment of multiple diseases and disorders of the CNS.[38]

Targacept has three drug candidates that are in clinical trials; AZD3480 (TC-1734) for ADHD which is currently in phase II clinical trials, AZD1446 (TC-6683) for Alzheimer's disease in collaboration with AstraZeneca and TC-5619 for cognitive dysfunctions in schizophrenia.

Memory pharmaceuticals with its partner Roche has one drug candidate, MEM 3454 (RG3487), a partial agonist of the nicotinic α7 receptor, for Alzheimer's disease.[39][40]

Abbott Laboratories in partnership with NeuroSearch have two drug candidates in clinical trials, ABT-894, a selective α4β2 nicotine receptor agonist, for ADHD and ABT-560, a neuronal nicotinic receptor modulator, which was selected by Abbott in 2006 as a new development candidate for cognitive dysfunctions.[41]

EnVivo pharmaceuticals has one drug candidate in clinical trials, EVP-6124, a selective α7 nicotine receptor agonist for Alzheimer's disease and schizophrenia and one follow-up compound, EVP-4473, that has successfully completed pre-clinical development.[42]

See also

References

  1. ↑ 1.0 1.1 Matera, Carlo; Papotto, Claudio; Dallanoce, Clelia; De Amici, Marco (August 2023). "Advances in small molecule selective ligands for heteromeric nicotinic acetylcholine receptors" (in en). Pharmacological Research 194. doi:10.1016/j.phrs.2023.106813. PMID 37302724. https://linkinghub.elsevier.com/retrieve/pii/S104366182300169X. 
  2. ↑ Henningfield, Jack E; Zeller, Mitch (2006), "Nicotine psychopharmacology research contributions to United States and global tobacco regulation: a look back and a look forward", Psychopharmacology 184 (3–4): 286–291, doi:10.1007/s00213-006-0308-4, PMID 16463054 
  3. ↑ 3.0 3.1 Haroutunian, Vahram; Barnes, Edward; Davis, KL (1985), "Cholinergie modulation of memory in rats", Psychopharmacology 87 (3): 266–271, doi:10.1007/BF00432705, PMID 3001803 
  4. ↑ 4.0 4.1 4.2 4.3 4.4 Buccafusco, J. J. (2004), "Neuronal nicotinic receptor subtypes: defining therapeutic targets", Molecular Interventions 4 (5): 285–295, doi:10.1124/mi.4.5.8, PMID 15471911, http://molinterv.aspetjournals.org/cgi/reprint/4/5/285.pdf, retrieved 2009-12-21 
  5. ↑ Buccafusco, J. J.; Jackson, W. J.; Terry Jr, AV; Marsh, KC; Decker, MW; Arneric, SP (1995), "Improvement in performance of a delayed matching-to-sample task by monkeys following ABT-418: a novel cholinergic channel activator for memory enhancement", Psychopharmacology 120 (3): 256–266, doi:10.1007/BF02311172, PMID 8524972 
  6. ↑ Ludwig, J.; Höffle-Maas, A. (2010), "Localization by site-directed mutagenesis of a galantamine binding site on α7 nicotinic acetylcholine receptor extracellular domain", Journal of Receptors and Signal Transduction 30 (6): 469–483, doi:10.3109/10799893.2010.505239, PMID 21062106 
  7. ↑ Liu, Zhaoping; Zhang, J; Berg, Darwin K. (2007), "Role of endogenous nicotinic signaling in guiding neuronal development", Biochemical Pharmacology 74 (8): 1112–1119, doi:10.1016/j.bcp.2007.05.022, PMID 17603025 
  8. ↑ 8.0 8.1 Gotti, C.; Clementi, F. (2004), "Neuronal nicotinic receptors: from structure to pathology", Progress in Neurobiology 74 (6): 363–396, doi:10.1016/j.pneurobio.2004.09.006, PMID 15649582 
  9. ↑ 9.0 9.1 9.2 Paterson, David; Nordberg, Agneta (2000), "Neuronal nicotinic receptors in the human brain", Progress in Neurobiology 61 (1): 75–111, doi:10.1016/s0301-0082(99)00045-3, PMID 10759066 
  10. ↑ Sala, F.; Nistri, A.; Criado, M. (2008), "Nicotinic acetylcholine receptors of adrenal chromaffin cells", Acta Physiologica 192 (2): 203–212, doi:10.1111/j.1748-1716.2007.01804.x, PMID 18005395, http://www3.interscience.wiley.com/cgi-bin/fulltext/119423079/PDFSTART 
  11. ↑ Itier, Valérie; Bertrand, Daniel (2001), "Neuronal nicotinic receptors: from protein structure to function", FEBS Letters 504 (3): 118–125, doi:10.1016/S0014-5793(01)02702-8, PMID 11532443 
  12. ↑ Arias, Hugo R. (1997), "Topology of ligand binding sites on the nicotinic acetylcholine receptor", Brain Research Reviews 25 (2): 133–191, doi:10.1016/S0165-0173(97)00020-9, PMID 9403137 
  13. ↑ 13.0 13.1 13.2 13.3 Haydar, Simon N.; Ghiron, Chiara; Bettinetti, Laura; Bothman, Hendrick; Comery, Thomas A.; Dunlop, John; La Rosa, Salvatore; Micco, Iolanda et al. (2009), "SAR and biological evaluation of SEN12333/WAY-317538: Novel alpha 7 nicotinic acetylcholine receptor agonist", Bioorganic & Medicinal Chemistry 17 (14): 5247–5258, doi:10.1016/j.bmc.2009.05.040, PMID 19515567 
  14. ↑ Brunton, Laurence L.; Lazo, John S.; Parker, Keith L., eds. (2006), Goodman & Gilman's The Pharmacological Basis of Therapeutics (11 ed.), McGRAW HILL, ISBN 978-0-07-142280-2 
  15. ↑ Cite error: Invalid <ref> tag; no text was provided for refs named Lindstrom_2003
  16. ↑ Unwin, Nigel (2004), "Refined Structure of the Nicotinic Acetylcholine Receptor at 4 A° Resolution", Journal of Molecular Biology 346 (4): 967–989, doi:10.1016/j.jmb.2004.12.031, PMID 15701510 
  17. ↑ Cassels, Bruce K.; Bermúdez, Isabel; Dajas, Federico; Abin-Carriquiry, J. Andrés; Wonnacott, Susan (2005), "From ligand design to therapeutic efficacy: the challenge for nicotinic receptor research", Drug Discovery Today 10 (23–24): 1657–1665, doi:10.1016/S1359-6446(05)03665-2, PMID 16376826 
  18. ↑ Matera, Carlo; Papotto, Claudio; Dallanoce, Clelia; De Amici, Marco (August 2023). "Advances in small molecule selective ligands for heteromeric nicotinic acetylcholine receptors" (in en). Pharmacological Research 194. doi:10.1016/j.phrs.2023.106813. PMID 37302724. https://linkinghub.elsevier.com/retrieve/pii/S104366182300169X. 
  19. ↑ Gotti, C.; Fornasari, D.; Clementi, F. (1997), "Human Neuronal Nicotinc Receptors", Progress in Neurobiology 53 (2): 199–237, doi:10.1016/S0301-0082(97)00034-8, PMID 9364611 
  20. ↑ Tøndera, Janne E.; Olesena, Preben H.; Hansena, John Bondo; Begtrupb, Mikael; Petterssona, Ingrid (2001), "An improved nicotinic pharmacophore and a stereoselective CoMFA-model for nicotinic agonists acting at the central nicotinic acetylcholine receptors labelled by [3H]-N-methylcarbamylcholine", Journal of Computer-Aided Molecular Design 15 (3): 247–258, doi:10.1023/A:1008140021426, PMID 11289078, Bibcode: 2001JCAMD..15..247T 
  21. ↑ Cooper, Julia C.; Gutbrod, Oliver; Witzemann, Veit; Methfessel, Christoph (1996), "Pharmacology of the nicotinic acetylcholine receptor from fetal rat muscle expressed in Xenopus oocytes", European Journal of Pharmacology 309 (3): 287–298, doi:10.1016/0014-2999(96)00294-4, PMID 8874153 
  22. ↑ Carter, Chris R.J.; Cao, Liren; Kawai, Hideki; Smith, Peter A.; Dryden, William F.; Raftery, Michael A.; Dunn, Susan M.J. (2007), "Chain length dependence of the interactions of bisquaternary ligands with the Torpedo nicotinic acetylcholine receptor", Biochemical Pharmacology 73 (3): 417–426, doi:10.1016/j.bcp.2006.10.011, PMID 17118342 
  23. ↑ Charton, Yves; Guillonneau, Claude.; Lockhart, Brian; Lestageb, Pierre; Goldsteina, Solo (2008), "Preparation and affinity profile of novel nicotinic ligands", Bioorganic & Medicinal Chemistry Letters 18 (6): 2188–2193, doi:10.1016/j.bmcl.2007.12.075, PMID 18262785 
  24. ↑ Walker, Daniel P.; Wishka, Donn G.; Piotrowski, David W.; Jia, Shaojuan; Reitz, Steven C.; Yates, Karen M.; Myers, Jason K.; Vetman, Tatiana N. et al. (2006), "Design, synthesis, structure–activity relationship, and in vivo activity of azabicyclic aryl amides as a7 nicotinic acetylcholine receptor agonists", Bioorganic & Medicinal Chemistry 14 (24): 8219–8248, doi:10.1016/j.bmc.2006.09.019, PMID 17011782 
  25. ↑ http://www.envivopharma.com - Nicotinic Alpha7 Acetylcholine Receptor Agonist Program
  26. ↑ 26.0 26.1 Rollema, H.; Chambers, L.K; Coe, J.W.; Glowa, J.; Hurst, R.S.; Lebel, L.A; Lu, Y.; Mansbach, R.S. et al. (2007), "Pharmacological profile of the α4β2 nicotinic acetylcholine receptor partial agonist varenicline, an effective smoking cessation aid", Neuropharmacology 52 (3): 985–994, doi:10.1016/j.neuropharm.2006.10.016, PMID 17157884 
  27. ↑ 27.0 27.1 "CHAMPIX 0.5 mg film-coated tablets; CHAMPIX 1 mg film-coated tablets - Summary of Product Characteristics (SmPC) - (eMC)". http://emc.medicines.org.uk/medicine/19045/SPC/CHAMPIX0.5mgfilm-coatedtablets;CHAMPIX1mgfilm-coatedtablets/. 
  28. ↑ Greenblatt, H.M.; Kryger, G.; Lewis, T.; Silman, I.; Sussman, J.L (1999), "Structure of acetylcholinesterase complexed with (-)-galanthamine at 2.3 angstrom resolution", FEBS Letters 463 (3): 321–326, doi:10.1016/S0014-5793(99)01637-3, PMID 10606746 
  29. ↑ "Reminyl XL 8mg, 16mg and 24mg prolonged release capsules - Summary of Product Characteristics (SmPC) - (eMC)". http://emc.medicines.org.uk/medicine/16219/SPC/ReminylXL8mg,16mgand24mgprolongedreleasecapsules. 
  30. ↑ Dani, John A.; Biasi, Mariella De (2001), "Cellular mechanisms of nicotine addiction", Pharmacology Biochemistry and Behavior 70 (4): 439–446, doi:10.1016/S0091-3057(01)00652-9, PMID 11796143 
  31. ↑ 31.0 31.1 31.2 31.3 Rang, H. P. (2003), Pharmacology, Edinburgh: Churchill Livingstone, ISBN 978-0-443-07145-4  Page 149
  32. ↑ XI, Zheng-xiong; Spiller, Krista; Gardner, Eliot L. (2009), "Mechanism-based medication development for the treatment of nicotine dependence", Acta Pharmacol Sin 30 (6): 723–739, doi:10.1038/aps.2009.46, ProQuest 213027402, PMID 19434058 
  33. ↑ "Miostat FDA label". December 2003. https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/16968s022lbl.pdf. 
  34. ↑ Tuba, Zoltan; Maho, Sandor; Vizi, E. Sylvester (2002), "Synthesis and Structure-Activity Relationships of Neuromuscular Blocking Agents", Current Medicinal Chemistry 9 (16): 1507–1536, doi:10.2174/0929867023369466, ProQuest 215095660, PMID 12171561 
  35. ↑ "Anectine Injection - Summary of Product Characteristics (SmPC) - (eMC)". http://emc.medicines.org.uk/medicine/704/SPC/AnectineInjection/. 
  36. ↑ Carroll, F. Ivy (2004), "Epibatidine structure-activity relationships", Bioorganic & Medicinal Chemistry Letters 14 (8): 1889–1896, doi:10.1016/j.bmcl.2004.02.007, PMID 15050621 
  37. ↑ Unless else specified in boxes, then reference is: Table 10-3 in: Rod Flower; Humphrey P. Rang; Maureen M. Dale; Ritter, James M. (2007), Rang & Dale's pharmacology, Edinburgh: Churchill Livingstone, ISBN 978-0-443-06911-6 
  38. ↑ Matera, Carlo; Papotto, Claudio; Dallanoce, Clelia; De Amici, Marco (August 2023). "Advances in small molecule selective ligands for heteromeric nicotinic acetylcholine receptors" (in en). Pharmacological Research 194. doi:10.1016/j.phrs.2023.106813. PMID 37302724. https://linkinghub.elsevier.com/retrieve/pii/S104366182300169X. 
  39. ↑ "Roche - Pharmaceuticals Pipeline". http://www.roche.com/research_and_development/pipeline/roche_pharma_pipeline.htm. 
  40. ↑ "Memory Pharmaceuticals Achieves Enrollment Goal For Phase 2 Study Of MEM 3454 In Cognitive Impairment Associated With Schizophrenia". http://www.medicalnewstoday.com/articles/130080.php. 
  41. ↑ "Drug Development". http://www.neurosearch.dk/Default.aspx?ID=30. 
  42. ↑ "Programs - EnVivo". http://www.envivopharma.com/template/5_5_1.html. 



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