The behavioral profile of the potent and selective mGlu5 receptor antagonist 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) in rodent models of anxiety.
Previous reports have demonstrated the anxiolytic effect of the potent and systemically active metabotropic glutamate subtype 5 (mGlu5) receptor antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) in rodents. Here, we present evidence for the anxiolytic activity of a novel mGlu5 receptor antagonist, 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP), in rats and compare its profile to the benzodiazepine receptor agonist diazepam. MTEP occupied mGlu5 receptors in a dose-dependent manner with essentially full receptor occupancy at the highest dose tested (10 mg/kg, i.p.). At doses appropriate for mGlu5 receptor-mediated effects, MTEP significantly reduced fear-potentiated startle and increased punished responding in a modified Geller-Seifter conflict model consistent with an anxiolytic-like profile. In both models, the magnitude of the anxiolytic-like response was similar to that seen with diazepam. In contrast, MTEP decreased unpunished responding to a lesser extent than diazepam and had no effect on rotarod performance when administered either alone or in combination with ethanol. Repeated dosing with MTEP in this model eliminated the increase in punished responding observed with acute dosing. The present results suggest that mGlu5 receptor antagonists lack the side effects seen with benzodiazepines, such as sedation and ethanol interaction, and provide insight into a possible role for mGlu5 receptor antagonists in the modulation of mood disorders.
Merck Research Laboratories, San Diego, CA, USA. Christopher_busse@merck.com
Chris S
CS
Busse
Jesse
J
Brodkin
David
D
Tattersall
Jeffery J
JJ
Anderson
Noelle
N
Warren
Lida
L
Tehrani
Linda J
LJ
Bristow
Mark A
MA
Varney
Nicholas D P
ND
Cosford
D000818:Animals; D001007:Anxiety / Q000188:drug therapy* / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008297:Male; D051379:Mice; D011725:Pyridines / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D013844:Thiazoles / Q000737:chemistry / Q000378:metabolism / Q000627:therapeutic use*
C472365:3-((2-methyl-1,3-thiazol-4-yl)ethynyl)pyridine; D011725:Pyridines; D064529:Receptor, Metabotropic Glutamate 5; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles