3-[(2-Methyl-1,3-thiazol-4-yl)ethynyl]-pyridine: a potent and highly selective metabotropic glutamate subtype 5 receptor antagonist with anxiolytic activity.
2-Methyl-6-(phenylethynyl)pyridine (3), a potent noncompetitive mGlu5 receptor antagonist widely used to characterize the pharmacology of mGlu5 receptors, suffers from a number of shortcomings as a therapeutic agent, including off-target activity and poor aqueous solubility. Seeking to improve the properties of 3 led to the synthesis of compound 9, a highly selective mGlu5 receptor antagonist that is 5-fold more potent than 3 in the rat fear-potentiated startle model of anxiety.
Cosford
Nicholas D P
ND
Merck Research Laboratories, MRLSDB2, 3535, General Atomics Court, San Diego, California 92121, USA. nicholas_cosford@merck.com
Tehrani
Lida
L
Roppe
Jeffrey
J
Schweiger
Edwin
E
Smith
Nicholas D
ND
Anderson
Jeffrey
J
Bristow
Linda
L
Brodkin
Jesse
J
Jiang
Xiaohui
X
McDonald
Ian
I
Rao
Sara
S
Washburn
Mark
M
Varney
Mark A
MA
D014151:Anti-Anxiety Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001007:Anxiety / Q000523:psychology; D001921:Brain / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D018691:Excitatory Amino Acid Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005239:Fear / Q000187:drug effects; D006801:Humans; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013216:Reflex, Startle / Q000187:drug effects; D013329:Structure-Activity Relationship
D014151:Anti-Anxiety Agents; D018691:Excitatory Amino Acid Antagonists; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D002118:Calcium