GABAB receptor allosteric modulators exhibit pathway‐dependent and species‐selective activity. Issue 2 (24th March 2017)

• Record Type: Journal Article
• Authors: Sturchler, Emmanuel; Li, Xia; de Lourdes Ladino, Maria; Kaczanowska, Kasia; Cameron, Michael; Griffin, Patrick R.; Finn, M. G.; Markou, Athina; McDonald, Patricia
• Is Part Of: Pharmacology research & perspectives. Volume 5:Issue 2(2017)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2017-03-24
• Subjects: Allosteric modulator -- biased signaling -- functional selectivity -- GABAB receptor -- ortholog selectivity; Pharmacology -- Periodicals; Drug development -- Periodicals; 615.105
• DOI: 10.1002/prp2.288
• Languages: English
• ISSNs: 2052-1707

Abstract

Abstract: Positive modulation of the GABAB receptor (GABAB R) represents a potentially useful therapeutic approach for the treatment of nicotine addiction. The positive allosteric modulators (PAMs) of GABAB R GS39783 and BHF177 enhance GABA‐stimulated [ 35 S]GTP γ 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 GABAB R‐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 GABAB R allosteric modulators exhibit species‐dependent activity. Collectively, these data will be useful in guiding the development of GABAB R 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.