Recent Advances on GABAB Receptor Positive Allosteric Modulators as Potential Pharmacotherapies for Alcohol Use Disorder

To date, ten different positive allosteric modulators (PAMs) of the GABAB receptor have been tested in laboratory rodents for their suppressing effects on a series of alcohol-related behaviors. This list includes CGP7930, GS39783, BHF177, rac-BHFF, ADX71441, CMPPE, COR659, ASP8062, KK-92A, and ORM-27669. The large body of collected data indicates a remarkable similarity in GABAB-PAM effects: all compounds reduced, or even suppressed, excessive alcohol drinking, relapse- and binge-like drinking, operant oral alcohol self-administration, reinstatement of alcohol seeking, and alcohol-induced hyperlocomotion and conditioned place preference in mice and rats exposed to validated experimental procedures that measure the reinforcing, motivational, rewarding, and stimulatory effects of alcohol. Aspects with translational value include large separation between the pharmacological and toxicological effects, limited development of tolerance, comparable efficacy in both sexes, and efficacy retained after per os administration. The current clinical testing of ASP8062 will prove to what extent these data may translate to patients with alcohol use disorder.