Discovery and SAR of novel mGluR5 non-competitive antagonists not based on an MPEP chemotype.
This Letter describes the discovery and SAR of three novel series of mGluR5 non-competitive antagonists/negative allosteric modulators (NAMs) not based on manipulation of an MPEP/MTEP chemotype. This work demonstrates fundamentally new mGluR5 NAM chemotypes with submicromolar potencies, and the first example of a mode of pharmacology 'switch' to provide PAMs with a non-MPEP scaffold.
Rodriguez
Alice L
AL
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Williams
Richard
R
Zhou
Ya
Y
Lindsley
Stacey R
SR
Le
Uyen
U
Grier
Mark D
MD
Weaver
C David
CD
Conn
P Jeffrey
PJ
Lindsley
Craig W
CW
D000494:Allosteric Regulation; D055808:Drug Discovery; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D020128:Inhibitory Concentration 50; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
C578935:GRM5 protein, human; D006575:Heterocyclic Compounds, 3-Ring; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate