KK-92A, a novel GABAB receptor positive allosteric modulator, attenuates nicotine self-administration and cue-induced nicotine seeking in rats

GABAB receptors (GABABR) 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. GABABR positive allosteric modulators (PAMs) have shown promise as potential anti-addictive therapies, as they lack the sedative and muscle relaxant properties of full GABAB receptor agonists such as baclofen. The present study was aimed at developing novel, selective, and potent GABABR PAMs with efficacy on abuse-related effects of nicotine. We synthetized ~100 analogs of BHF177, a GABABR 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 GABABR. Interestingly, our results revealed the existence of pathway-selective differential modulation of GABABR signaling by the structurally related GABABR 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. These results indicate that KK-92A is a selective GABABR PAM with efficacy in inhibition of the primary reinforcing and incentive motivational effects of nicotine, and attenuation of nicotine seeking, further confirming that GABABR PAMs may be useful antismoking medications.