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Discovery and Characterization of a Novel Subtype‐Selective M1 Allosteric Agonist for the Treatment of Alzheimer's Disease
Author(s) -
Lebois Evan P,
Bridges Thomas M,
Kennedy J Phillip,
Xiang Zixiu,
Jadhav Satyawan B,
Yin Huiyong,
Jones Carrie K,
Conn P Jeffrey,
Weaver C David,
Lindsley Craig W
Publication year - 2009
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.23.1_supplement.756.12
Subject(s) - agonist , muscarinic acetylcholine receptor , allosteric regulation , pharmacology , allosteric modulator , cholinergic , neuroscience , acetylcholine , muscarinic agonist , muscarinic acetylcholine receptor m1 , drug discovery , chemistry , receptor , medicine , biology , biochemistry
The muscarinic acetylcholine receptors are a family of five cholinergic GPCRS, designated M 1 ‐M 5 , located throughout the central nervous system (CNS) and periphery. Due to impaired hippocampal‐dependent learning, the M 1 muscarinic receptor has long been implicated in the pathophysiology of Alzheimer's Disease (AD). While the M 1 receptor has remained a Phase III clinically‐validated target for obtaining cognitive efficacy in AD, all efforts heretofore have not met FDA approval due to a lack of muscarinic selectivity, giving rise to severe cholinergic side effects such as poor GI tolerance. The present work reports the discovery of the first truly subtype‐selective M 1 allosteric agonist, VU0184670 which possesses EC 50 and Ach max values of 150nM and 85%, respectively, with exclusive selectivity versus M 2 ‐M 5 . In addition, VU0184670 was found to robustly potentiate NMDAR current in rat hippocampal slices. Favorable pharmacokinetics were observed following intraperitoneal dosing of an analog VU0357017 in rats at 10 mg/kg, while PanLabs analysis showed no significant off‐target binding at 10μM, providing a clear window with which to perform in vivo studies. The discovery of a potent, truly selective M1 allosteric agonist represents a significant breakthrough for AD treatment and will provide a critical basic tool to allow dissection of M 1 ‐mediated efficacy in other disease states such as Schizophrenia.