Synthesis and SAR of a mGluR5 allosteric partial antagonist lead: unexpected modulation of pharmacology with slight structural modifications to a 5-(phenylethynyl)pyrimidine scaffold.
This Letter describes the synthesis and SAR, developed through an iterative analogue library approach, of a mGluR5 allosteric partial antagonist lead based on a 5-(phenylethynyl)pyrimidine scaffold. With slight structural modifications to the distal phenyl ring, analogues demonstrated a range of pharmacological activities from mGluR5 partial antagonism to full antagonism/negative allosteric modulation to positive allosteric modulation.
Department of Pharmacology, Vanderbilt University Medical Center, 12415D MRBIV, Nashville, TN 37232, USA.
Sameer
S
Sharma
Alice L
AL
Rodriguez
P Jeffrey
PJ
Conn
Craig W
CW
Lindsley
D000494:Allosteric Regulation / Q000187:drug effects; D000495:Allosteric Site; D000818:Animals; D001667:Binding, Competitive; D002626:Chemistry, Pharmaceutical / Q000379:methods; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008024:Ligands; D008956:Models, Chemical; D011743:Pyrimidines / Q000737:chemistry; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013329:Structure-Activity Relationship; D013997:Time Factors
C578935:GRM5 protein, human; C578937:Grm5 protein, rat; D008024:Ligands; D011743:Pyrimidines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate