2. Academic Validation
  3. GABAB receptor allosteric modulators exhibit pathway-dependent and species-selective activity

GABAB receptor allosteric modulators exhibit pathway-dependent and species-selective activity

  • Pharmacol Res Perspect. 2017 Mar 24;5(2):e00288. doi: 10.1002/prp2.288.
Emmanuel Sturchler 1,  Xia Li 2,  Maria de Lourdes Ladino 3,  Kasia Kaczanowska 4,  Michael Cameron 1,  Patrick R Griffin 1,  M G Finn 5,  Athina Markou 2,  Patricia McDonald 1
Affiliations

Affiliations

  • 1 Department of Molecular Therapeutics The Scripps Research Institute 130 Scripps way Jupiter Florida 33458.
  • 2 Department of Psychiatry University of California San Diego 9500 Gilman Drive La Jolla California 92093.
  • 3 Department of Molecular Therapeutics The Scripps Research Institute 130 Scripps way Jupiter Florida 33458; Present address: School of Medicine Vanderbilt University 2215 Garland Ave Nashville Tennessee 37232.
  • 4 Department of Chemistry The Scripps Research Institute 10550 North Torrey Pines Road La Jolla California 92037; Present address: Department of Chemistry University of California San Diego, 9500 Gilman Drive La Jolla California 92093.
  • 5 Department of Chemistry The Scripps Research Institute 10550 North Torrey Pines Road La Jolla California 92037; Present address: Georgia Institute of Technology School of Chemistry and Biochemistry 901 Atlantic Drive Atlanta Georgia 30332.
PMID: 28357120 DOI: 10.1002/prp2.288
Abstract

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

Keywords

Allosteric modulator; GABAB receptor; biased signaling; functional selectivity; ortholog selectivity.

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