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.
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.
Bridges
Thomas M
TM
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Kennedy
J Phillip
JP
Cho
Hyekyung P
HP
Breininger
Micah L
ML
Gentry
Patrick R
PR
Hopkins
Corey R
CR
Conn
P Jeffrey
PJ
Lindsley
Craig W
CW
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
D043643:Receptor, Muscarinic M1; D043587:Receptor, Muscarinic M3; D043642:Receptor, Muscarinic M5