GABA_Breceptor allosteric modulators exhibit pathway-dependent and species-selective activity

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.

Simultaneous activation of muscarinic and GABAB receptors as a bidirectional target for novel antipsychotics

“…Here, the mACh-GABA B combination may be proposed for the treatment of positive and cognitive disturbances, but not negative symptoms. Pharmacokinetic experiments that were performed confirmed high penetration capacity for GS39783 when administered independently at a high dose and in combination with activators of muscarinic M 1 , M 4 , M 5 receptors according to Sturchler et al [42]. Subsequently, we did not observe any brain penetration decrease for VU0152100 or VU0357017 when administered concomitantly with GS39783, which probably excludes the possibility of drug-drug interaction and confirms their independent transport though the Blood Brain Barrier.…”

The GABAB Receptor—Structure, Ligand Binding and Drug Development

“…In theory, this can result in a variety of signaling profiles based on the specific allosteric and orthosteric compound in combination or even alone, stabilizing a certain receptor conformation [66]. Biased agonism is well characterized for class A GPCRs and class C mGluRs [67,68], and was recently described for GABA B -R where the PAMs GS39783 and BHF177 were found to have functional selectivity for intracellular signaling pathways in various functional assays [69].…”

Loss of constitutive functional γ‐aminobutyric acid type A‐B receptor crosstalk in layer 5 pyramidal neurons of human epileptic temporal cortex

“…In rat cell lines and native neurons, a crosstalk between PKC and PKA has been described in the context of transduction mechanisms triggered by GABA B R activation. 33 31 The absence of a PKC effect on the baclofen-induced kinetic modulation in humans confirms differences in the modulation of GABA B R transduction mechanisms across species.…”

“…31 The absence of a PKC effect on the baclofen-induced kinetic modulation in humans confirms differences in the modulation of GABA B R transduction mechanisms across species. 33…”