Phenyl-tetrazolyl acetophenones: discovery of positive allosteric potentiatiors for the metabotropic glutamate 2 receptor.
Herein we disclose the discovery of a new class of positive allosteric potentiators of the metabotropic glutamate receptor 2 (mGlu2), phenyl-tetrazolyl acetophenones, e.g. 1-(2-hydroxy-3-propyl-4-[4-[4-(2H-tetrazol-5-yl)phenoxy]butoxy]phenyl) ethanone (4). These potentiators were shown to have no effect in the absence of glutamate as well as no effect at mGlu3 or the other mGlu receptors. The compounds were also evaluated in rodent models with potential relevance for schizophrenia, and 4 was shown to have activity in the inhibition of ketamine-induced norepinephrine release and ketamine-induced hyperactivity. This represents the first example of the efficacy of mGlu2 receptor potentiators in these models.
Pinkerton
Anthony B
AB
Merck Research Laboratories-San Diego, 3535 General Atomics Court, San Diego, California 92121, USA. anthony_pinkerton@merck.com
Vernier
Jean-Michel
JM
Schaffhauser
Hervé
H
Rowe
Blake A
BA
Campbell
Una C
UC
Rodriguez
Dana E
DE
Lorrain
Daniel S
DS
Baccei
Christopher S
CS
Daggett
Lorrie P
LP
Bristow
Linda J
LJ
D000098:Acetophenones / Q000138:chemical synthesis* / Q000494:pharmacology*; D000494:Allosteric Regulation; D000818:Animals; D001519:Behavior / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D018698:Glutamic Acid / Q000494:pharmacology; D006948:Hyperkinesis / Q000188:drug therapy; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists*; D012559:Schizophrenia / Q000188:drug therapy; D013329:Structure-Activity Relationship
D000098:Acetophenones; D018094:Receptors, Metabotropic Glutamate; C108822:metabotropic glutamate receptor 2; D018698:Glutamic Acid; D009638:Norepinephrine