title: Chemical lead optimization of a pan G(q) mAChR M(1), M(3), M(5) positive allosteric modulator (PAM) lead. Part I: Development of the first highly selective M(5) PAM.
abstract: This Letter describes a chemical lead optimization campaign directed at VU0238429, the first M(5)-preferring positive allosteric modulator (PAM), discovered through analog work around VU0119498, a pan G(q) mAChR M(1), M(3), M(5) PAM. An iterative library synthesis approach delivered the first selective M(5) PAM (no activity at M(1)-M(4) @ 30microM), and an important tool compound to study the role of M(5) in the CNS.
authors.affiliation: Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Bridges
authors.forename: J Phillip
authors.initials: JP
authors.lastname: Kennedy
authors.forename: Hyekyung P
authors.initials: HP
authors.lastname: Cho
authors.forename: Micah L
authors.initials: ML
authors.lastname: Breininger
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Gentry
authors.forename: Corey R
authors.initials: CR
authors.lastname: Hopkins
authors.forename: P Jeffrey
authors.initials: PJ
authors.lastname: Conn
authors.forename: Craig W
authors.initials: CW
authors.lastname: Lindsley
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D057166:High-Throughput Screening Assays; D051379:Mice; D018345:Mice, Knockout; D043643:Receptor, Muscarinic M1 / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D043587:Receptor, Muscarinic M3 / Q000819:agonists / Q000378:metabolism*; D043642:Receptor, Muscarinic M5 / Q000819:agonists / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D043643:Receptor, Muscarinic M1; D043587:Receptor, Muscarinic M3; D043642:Receptor, Muscarinic M5