Chemical lead optimization of a pan Gq mAChR M1, M3, M5 positive allosteric modulator (PAM) lead. Part II: development of a potent and highly selective M1 PAM.
This Letter describes a chemical lead optimization campaign directed at VU0119498, a pan G(q) mAChR M(1), M(3), M(5) positive allosteric modulator (PAM) with the goal of developing a selective M(1) PAM. An iterative library synthesis approach delivered a potent (M(1) EC(50)=830 nM) and highly selective M(1) PAM (>30 microM vs M(2)-M(5)).
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Thomas M
TM
Bridges
J
J
Phillip Kennedy
Meredith J
MJ
Noetzel
Micah L
ML
Breininger
Patrick R
PR
Gentry
P Jeffrey
PJ
Conn
Craig W
CW
Lindsley
D000494:Allosteric Regulation; D018678:Cholinergic Agents / Q000737:chemistry* / Q000494:pharmacology; D015195:Drug Design; D011976:Receptors, Muscarinic / Q000187:drug effects*; D013329:Structure-Activity Relationship
D018678:Cholinergic Agents; D011976:Receptors, Muscarinic