Synthesis and SAR of a novel metabotropic glutamate receptor 4 (mGlu4) antagonist: unexpected 'molecular switch' from a closely related mGlu4 positive allosteric modulator.
Herein we report the discovery and SAR of a novel antagonist of metabotropic glutamate receptor 4 (mGlu(4)). The antagonist was discovered via a molecular switch from a closely related mGlu(4) positive allosteric modulator (PAM). This antagonist (VU0448383) displays an IC(50) value of 8.2±0.4 μM and inhibits an EC(80) glutamate response by 63.1±6.6%.
Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
Thomas
T
Utley
Dustin
D
Haddenham
James M
JM
Salovich
Rocio
R
Zamorano
Paige N
PN
Vinson
Craig W
CW
Lindsley
Corey R
CR
Hopkins
Colleen M
CM
Niswender
D000494:Allosteric Regulation; D000818:Animals; D002478:Cells, Cultured; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D011725:Pyridines; D018094:Receptors, Metabotropic Glutamate; C571401:VU0448383; C108823:metabotropic glutamate receptor 4