GABA receptor allosteric modulators exhibit pathway-dependent and species-selective activity.

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.