Discovery of novel heteroarylazoles that are metabotropic glutamate subtype 5 receptor antagonists with anxiolytic activity.
The highly potent, selective, and brain-penetrant metabotropic glutamate subtype 5 (mGlu5) receptor antagonists 3-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (47) and 3-fluoro-5-(5-pyridin-2-yl-2H-tetrazol-2-yl)benzonitrile (48) are reported. Compound 47 is active in the rat fear-potentiated startle (FPS) model of anxiety with ED(50) = 5.4 mg/kg (po) when dosed acutely. In this model the anxiolytic effects of 47 rapidly tolerate on repeated dosing.
Roppe
Jeffrey
J
Smith
Nicholas D
ND
Huang
Dehua
D
Tehrani
Lida
L
Wang
Bowei
B
Anderson
Jeffrey
J
Brodkin
Jesse
J
Chung
Janice
J
Jiang
Xiaohui
X
King
Christopher
C
Munoz
Benito
B
Varney
Mark A
MA
Prasit
Petpiboon
P
Cosford
Nicholas D P
ND
D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D051381:Rats; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
D014151:Anti-Anxiety Agents; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate