title: GABABreceptor allosteric modulators exhibit pathway-dependent and species-selective activity.
abstract: Positive modulation of the GABABreceptor (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]GTPγS-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.
authors.affiliation: Department of Molecular Therapeutics The Scripps Research Institute 130 Scripps way Jupiter Florida 33458.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Sturchler
authors.affiliation: Department of Psychiatry University of California San Diego 9500 Gilman Drive La Jolla California 92093.
authors.forename: Xia
authors.initials: X
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Maria
authors.initials: M
authors.lastname: de Lourdes Ladino
authors.affiliation: 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.
authors.forename: Kasia
authors.initials: K
authors.lastname: Kaczanowska
authors.affiliation: Department of Molecular Therapeutics The Scripps Research Institute 130 Scripps way Jupiter Florida 33458.
authors.forename: Michael
authors.initials: M
authors.lastname: Cameron
authors.affiliation: Department of Molecular Therapeutics The Scripps Research Institute 130 Scripps way Jupiter Florida 33458.
authors.forename: Patrick R
authors.initials: PR
authors.lastname: Griffin
authors.affiliation: 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.
authors.forename: M G
authors.initials: MG
authors.lastname: Finn
authors.affiliation: Department of Psychiatry University of California San Diego 9500 Gilman Drive La Jolla California 92093.
authors.forename: Athina
authors.initials: A
authors.lastname: Markou
authors.affiliation: Department of Molecular Therapeutics The Scripps Research Institute 130 Scripps way Jupiter Florida 33458.
authors.forename: Patricia
authors.initials: P
authors.lastname: McDonald
keywords: Allosteric modulator; GABAB receptor; biased signaling; functional selectivity; ortholog selectivity