Nicotinic acetylcholine receptors: From basic science to therapeutics

被引:393
|
作者
Hurst, Raymond [1 ]
Rollema, Hans [2 ]
Bertrand, Daniel [3 ]
机构
[1] Pfizer Worldwide Res & Dev, Neurosci Res, Cambridge, MA 02139 USA
[2] Rollema Biomed Consulting, Mystic, CT 06355 USA
[3] HiQScreen Sarl, CH-1206 Geneva, Switzerland
关键词
Nicotinic acetylcholine receptors; Structure; Distribution; Function; Pharmacology; Therapeutics; SUBUNIT MESSENGER-RNA; INDUCED UP-REGULATION; ATTENTION-DEFICIT/HYPERACTIVITY DISORDER; POSITIVE ALLOSTERIC MODULATION; PARTIAL AGONISTS VARENICLINE; CORTICAL CHOLINERGIC INPUTS; FORCED SWIM TEST; IN-VITRO; SMOKING-CESSATION; ALPHA-7; RECEPTOR;
D O I
10.1016/j.pharmthera.2012.08.012
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Substantial progress in the identification of genes encoding for a large number of proteins responsible for various aspects of neurotransmitter release, postsynaptic detection and downstream signaling, has advanced our understanding of the mechanisms by which neurons communicate and interact. Nicotinic acetylcholine receptors represent a large and well-characterized family of ligand-gated ion channels that is expressed broadly throughout the central and peripheral nervous system, and in non-neuronal cells. With 16 mammalian genes identified that encode for nicotinic receptors and the ability of the subunits to form heteromeric or homomeric receptors, the repertoire of conceivable receptor subtype combinations is enormous and offers unique possibilities for the design and development of new therapeutics that target nicotinic acetylcholine receptors. The aim of this review is to provide the reader with recent insights in nicotinic acetylcholine receptors from genes, structure and function to diseases, and with the latest findings on the pharmacology of these receptors. Although so far only a few nicotinic drugs have been marketed or are in late stage development, much progress has been made in the design of novel chemical entities that are being explored for the treatment of various diseases, including addiction, depression, ADHD, cognitive deficits in schizophrenia and Alzheimer's disease, pain and inflammation. A pharmacological analysis of these compounds, including those that were discontinued, can improve our understanding of the pharmacodynamic and pharmacokinetic requirements for nicotinic 'drug-like' molecules and will reveal if hypotheses on therapies based on targeting specific nicotinic receptor subtypes have been adequately tested in the clinic. (C) 2012 Elsevier Inc. All rights reserved.
引用
收藏
页码:22 / 54
页数:33
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