GABA Receptor Allosteric Modulators Exhibit Pathway-dependent and Species-selective Activity

Overview

Journal Pharmacol Res Perspect

Date 2017 Mar 31

PMID 28357120

Citations 7

Authors

Emmanuel Sturchler

Xia Li

Maria de Lourdes Ladino

Kasia Kaczanowska

Michael Cameron

Patrick R Griffin

M G Finn

Athina Markou

Patricia McDonald

Affiliations

Soon will be listed here.

Abstract

Positive modulation of the GABA receptor (GABAR) represents a potentially useful therapeutic approach for the treatment of nicotine addiction. The positive allosteric modulators (PAMs) of GABAR GS39783 and BHF177 enhance GABA-stimulated [S]GTP S-binding, and have shown efficacy in a rodent nicotine self-administration procedure reflecting aspects of nicotine dependence. Interestingly, the structural related analog, NVP998, had no effect on nicotine self-administration in rats despite demonstrating similar pharmacokinetic properties. Extensive in vitro characterization of GS39783, BHF177, and NVP998 activity on GABAR-regulated signaling events, including modulation of cAMP, intracellular calcium levels, and ERK activation, revealed that these structurally related molecules display distinct pathway-specific signaling activities that correlate with the dissimilarities observed in rodent models and may be predictive of in vivo efficacy. Furthermore, these GABAR allosteric modulators exhibit species-dependent activity. Collectively, these data will be useful in guiding the development of GABAR allosteric modulators that display optimal in vivo efficacy in a preclinical model of nicotine dependence, and will identify those that have the potential to lead to novel antismoking therapies.

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