The New Compound GET73, N-[(4-trifluoromethyl)benzyl]4-methoxybutyramide, Regulates Hippocampal Aminoacidergic Transmission Possibly Via an Allosteric Modulation of mGlu5 Receptor. Behavioural Evidence of its “Anti-Alcohol” and Anxiolytic Properties

L.      Ferraro; A.      Loche; S.      Beggiato; M.   C.   Tomasini; T.      Antonelli; G.      Colombo; C.      Lobina; M.   A.M.   Carai; A.      Porcu; M.   P.   Castelli; F.      Clerici; A.   C.   Borelli; R.      Cacciaglia; S.      Tanganelli

Abstract

The present article attempts to provide, on the basis of data emerging from studies carried out in our laboratories, a summary of the chemical and pharmacological properties of the new compound N-[(4-trifluoromethyl)benzyl]4- methoxybutyramide (GET73). Particular emphasis is given to findings obtained in vivo and in vitro suggesting that an allosteric modulation of metabotropic glutamate receptor 5 (mGlu5 receptor) by GET73 may represent the mechanism underlying the effects of the compound produced on rat hippocampal glutamate and GABA transmission. Furthermore, behavioural findings demonstrating how this new compound reduces alcohol intake, displays anxiolytic properties, and influences spatial memory in rats are also summarized. Since mGlu5 receptors play an important role in regulating several central actions of drugs of abuse, and the hippocampus is a crucial brain area involved in addiction, anxiety, and spatial memory, a possible link between mGlu5 receptor allosteric modulation and the profiles of action of GET73 is proposed, although to date no studies have yet explored GET73 binding at the mGlu5 receptor orthosteric and/or allosteric sites.

Following a brief overview of glutamatergic neurotransmission, mGlu receptor structures and activation mechanisms, the general properties of mGlu5 receptor and its allosteric modulators are described in the first part of the review.

Keywords: Negative allosteric modulator, Positive allosteric modulator, Sardinian alcohol-preferring rats, Alcohol intake, Alcohol deprivation effect, Anxiety-related behaviours, Glutamate release, GABA release.