Rationale

GABA B receptors (GABA B R) play a critical role in GABAergic neurotransmission in the brain and are thought to be one of the most promising targets for the treatment of drug addiction. GABA B R positive allosteric modulators (PAMs) have shown promise as potential anti-addictive therapies, as they lack the sedative and muscle relaxant properties of full GABA B receptor agonists such as baclofen.

Objectives

The present study was aimed at developing novel, selective, and potent GABA B R PAMs with efficacy on abuse-related effects of nicotine.

Results

We synthetized ~100 analogs of BHF177, a GABA B R PAM that has been shown to inhibit nicotine taking and seeking, and tested their activity in multiple cell-based functional assays. Among these compounds, KK-92A displayed superior PAM properties at the GABA B R. Interestingly, our results revealed the existence of pathway-selective differential modulation of GABA B R signaling by the structurally related GABA B R allosteric modulators BHF177 and KK-92A. In vivo, similarly to BHF177, KK-92A inhibited intravenous nicotine self-administration under both fixed- and progressive-ratio schedules of reinforcement in rats. In contrast to BHF177, KK-92A had no effect on food self-administration. Furthermore, KK-92A decreased cue-induced nicotine-seeking behavior without affecting food seeking.

Conclusions