Nicotinic Agonists and Antagonists. Fig. 8. Structures of nAChR ligands discussed for pain.
reported to have analgesic activity, has an affinity for a7 nAChRs.
Since neither nicotine nor epibatidine can be used clinically owing to safety concerns at analgesic doses, synthetic nAChR agonists are being pursued as analgesics and most research has focused on selective a4b2 agonists. The a4b2 nAChR agonist ABT-594 (Fig. 8) is structurally related to epibatidine with similar analgesic potency, but its development was not pursued owing to limited tolera-bility. Similarly, the development of two other selective a4b2 nAChR agonists, TC-2696 (Fig. 8) and TC-6499 (structure not disclosed), which had shown analgesic efficacy in preclinical pain models, was halted because of lack of efficacy and an insufficient therapeutic index. More promising is a second-generation a4b2 full agonist, ABT-894 (structure not disclosed), which is currently under development for neuropathic pain.
While the clinical evidence for analgesic efficacy of selective a4b2 nAChR ligands is still limited, the possibility remains that the activity at other nAChR subtypes contributes to analgesic efficacy.
Our increased understanding of nAChR pharmacology and how agonists, partial agonists, and antagonists modulate the function of these receptors has led to the discovery of a large number of selective ligands that are being used either as tools for exploring the role(s) of nAChR subtypes or are in the preclinical or clinical stage of development as potential new pharmacotherapies. Several compounds represent promising new treatments for disorders in which nAChRs are thought to participate. However, the fact that to date very few nAChR ligands have been approved for clinical use illustrates the tremendous challenge of developing selective nicotinic compounds as novel medications without major side effects. The high degree of homology between the different receptor subtypes calls for a better knowledge of their function and distribution throughout the body and for the finding of subtype-selective compounds. In addition, high selectivity is essential for an acceptable side-effect profile to avoid interactions with peripheral muscle and ganglionic nAChR subtypes associated with cardiovascular, gastrointestinal, and respiratory adverse events. Clearly, progress in the development of novel drugs that target nAChR subtypes is dependent on the design and discovery of highly selective ligands with sufficient potency and adequate pharmacokinetic properties to have efficacy at doses at which selectivity is maintained.
HR and RSH are employees of Pfizer, Inc. DB was supported by the Swiss National Science Foundation. Editorial support was provided by Alexandra Bruce, PhD, of UBC Scientific Solutions, and was funded by Pfizer, Inc.
► Adverse Effect
► Alcohol Abuse and Dependence
► Alzheimer's Disease
► Anti-Parkinson Drugs
► Cognitive Enhancers
► Cognitive Enhancers: Novel Approaches
► Nicotine Dependence and Its Treatment
► Nicotinic Receptor
► Parkinson's Disease
► Partial Agonist
► Rodent Tests of Cognition
Albuquerque EX, Pereira EF, Alkondon M, Rogers SW (2009) Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol Rev 89:73-120 Arneric SP, Holladay M, Williams M (2007) Neuronal nicotinic receptors: a perspective on two decades of drug discovery research. Biochem Pharmacol 74:1092-1101 Benowitz NL (2009) Pharmacology of nicotine: addiction, smoking-induced disease, and therapeutics. Annu Rev Pharmacol Toxicol 49:57-71
Changeux JP, Edelstein SJ (2005) Allosteric mechanisms of signal transduction. Science 308:1424-1428 Cincotta SL, Yorek MS, Moschak TM, Lewis SR, Rodefer JS (2008) Selective nicotinic acetylcholine receptor agonists: potential therapies for neuropsychiatric disorders with cognitive dysfunction. Curr Opin Investig Drugs 9:47-56 Dani JA, Bertrand D (2007) Nicotinic acetylcholine receptors and nico-tinic cholinergic mechanisms of the central nervous system. Annu Rev Pharmacol Toxicol 47:699-729 Freedman R, Olincy A, Buchanan RW, Harris JG, Gold JM, Johnson L, Allensworth D, Guzman-Bonilla A, Clement B, Ball MP, Kutnick J, Pender V, Martin LF, Stevens KE, Wagner BD, Zerbe GO, Soti F, Kem WR (2008) Initial phase 2 trial of a nicotinic agonist in schizophrenia. Am J Psychiatry 165:1040-1047 Hogg RC, Bertrand D (2007) Partial agonists as therapeutic agents at neuronal nicotinic acetylcholine receptors. Biochem Pharmacol 73:459-468
Lape R, Colquhoun D, Sivilotti LG (2008) On the nature of partial agonism in the nicotinic receptor superfamily. Nature 454:722-727 Mukhtasimova N, Lee WY, Wang HL, Sine SM (2009) Detection and trapping of intermediate states priming nicotinic receptor channel opening. Nature 459:451-454 Picciotto MR, Addy NA, Mineur YS, Brunzell DH (2008) It is not ''either/ or'': activation and desensitization of nicotinic acetylcholine receptors both contribute to behaviors related to nicotine addiction and mood. Prog Neurobiol 84:329-342 QuikM, O'Leary K, Tanner CM (2008) Nicotine and Parkinson's disease:
implications for therapy. Mov Disord 23:1641-1652 Rollema H, Coe JW, Chambers LK, Hurst RS, Stahl SM, Williams KE (2007) Rationale, pharmacology and clinical efficacy of partial agonists of a4p2 nACh receptors for smoking cessation. Trends Pharmacol Sci 28:316-325
Rusted JM, Newhouse PA, Levin ED (2000) Nicotinic treatment for degenerative neuropsychiatric disorders such as Alzheimer's disease and Parkinson's disease. Behav Brain Res 113:121-129 Shytle RD, Silver AA, Lukas RJ, Newman MB, Sheehan DV, Sanberg PR (2002) Nicotinic acetylcholine receptors as targets for antidepres-sants. Mol Psychiatry 7:525-535 Wilens TE, Decker MW (2007) Neuronal nicotinic receptor agonists for the treatment of attention-deficit/hyperactivity disorder: focus on cognition. Biochem Pharmacol 74:1212-1223 Yang KC, Jin GZ, Wu J (2009) Mysterious a6-containing nAChRs: function, pharmacology, and pathophysiology. Acta Pharmacol Sin 30:740-751
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