Recombinant human receptors and functional assays in the discovery of altinicline (SIB-1508Y), a novel acetylcholine-gated ion channel (nAChR) agonist

Neuronal nicotinic acetylcholine receptors (nAChRs) are a class of ion channels with significant potential as molecular targets for the design of drugs to treat a variety of CNS disorders. The discovery that neuronal nAChRs are further subdivided into multiple subtypes suggests that drugs which act...

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Bibliographic Details
Published in:Pharmaceutica acta Helvetiae 2000-03, Vol.74 (2-3), p.125-130
Main Authors: Cosford, Nicholas D.P, Bleicher, Leo, Vernier, Jean-Michel, Chavez-Noriega, Laura, Rao, Tadimeti S, Siegel, Robert S, Suto, Carla, Washburn, Mark, Lloyd, G.Kenneth, McDonald, Ian A
Format: Article
Language:English
Subjects:
Altinicline
Ca2+ flux
Calcium - metabolism
Cognitive deficits
Dopamine - metabolism
Functional assays
Humans
Ion Channel Gating - drug effects
Ion Channels - drug effects
Ion Channels - metabolism
nAChR subtypes
Nicotine
Nicotinic acetylcholine receptors
Nicotinic Agonists - pharmacology
Parkinson's disease
Pyridines - pharmacology
Pyrrolidines - pharmacology
Receptors, Cholinergic - chemistry
Receptors, Cholinergic - drug effects
Recombinant human receptors
Recombinant Proteins
SIB-1765F
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Summary:Neuronal nicotinic acetylcholine receptors (nAChRs) are a class of ion channels with significant potential as molecular targets for the design of drugs to treat a variety of CNS disorders. The discovery that neuronal nAChRs are further subdivided into multiple subtypes suggests that drugs which act selectively at specific nAChR subtypes might effectively treat Parkinson's disease (PD), Alzheimer's disease (AD), schizophrenia, ADHD, depression, anxiety or pain without the accompanying adverse side effects associated with non-selective agents such as nicotine (1) and epibatidine. Altinicline (SIB-1508Y) is a novel, small molecule designed to selectively activate neuronal nAChRs and is undergoing clinical evaluation for the treatment of PD. It was selected from a series of compounds primarily on the basis of results from functional assays, including (a) measurement of Ca2+ flux in stable cell lines expressing specific recombinant human neuronal nAChR subtypes; (b) determination of in vitro and in vivo neurotransmitter release; (c) in vivo models of PD. Biological data on both altinicline and the series of compounds from which it was selected are reported.
ISSN:0031-6865
DOI:10.1016/S0031-6865(99)00024-2