title: Recombinant human receptors and functional assays in the discovery of altinicline (SIB-1508Y), a novel acetylcholine-gated ion channel (nAChR) agonist.
abstract: 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.
authors.affiliation: Merck Research Laboratories San Diego, La Jolla, CA 92037, USA.
authors.forename: N D
authors.initials: ND
authors.lastname: Cosford
authors.forename: L
authors.initials: L
authors.lastname: Bleicher
authors.forename: J M
authors.initials: JM
authors.lastname: Vernier
authors.forename: L
authors.initials: L
authors.lastname: Chavez-Noriega
authors.forename: T S
authors.initials: TS
authors.lastname: Rao
authors.forename: R S
authors.initials: RS
authors.lastname: Siegel
authors.forename: C
authors.initials: C
authors.lastname: Suto
authors.forename: M
authors.initials: M
authors.lastname: Washburn
authors.forename: G K
authors.initials: GK
authors.lastname: Lloyd
authors.forename: I A
authors.initials: IA
authors.lastname: McDonald
mesh_terms: D002118:Calcium / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D006801:Humans; D015640:Ion Channel Gating / Q000187:drug effects; D007473:Ion Channels / Q000187:drug effects / Q000378:metabolism*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D011950:Receptors, Cholinergic / Q000737:chemistry / Q000187:drug effects*; D011994:Recombinant Proteins
chemical_list: D007473:Ion Channels; D018722:Nicotinic Agonists; D011725:Pyridines; D011759:Pyrrolidines; D011950:Receptors, Cholinergic; D011994:Recombinant Proteins; C100989:altinicline maleate; D002118:Calcium; D004298:Dopamine