Boris Tabakoff, Lohocla Research Corporation, Aurora, CO U.S.A.
An advance in the treatment of any disease starts with a good idea or serendipitous findings or a combination of both. Lohocla started its journey in medication development through the rational design of novel molecules for treatment of chronic pain syndromes, but noted that one of its synthesized structural derivatives could selectively displace muscimol in a radioligand binding screening process. Electrophysiologic studies demonstrated that this derivative, given the acronym DCUK-OEt and a tradename of Nezavist, was a positive allosteric modulator (PAM) at the GABA-A receptor with properties distinguishing it from currently known PAMs. DCUK-OEt preferentially interacted with the 12/3 subunit combination which is found in the central amygdala and in the dentate gyrus. When tested in models of relapse drinking in rats, DCUK-OEt was an efficacious agent for reducing abstinence-induced increases in alcohol consumption and cue-induced alcohol consumption. The exciting pre-clinical work was, however, followed by highly necessary, but difficult, studies on developing formulations for optimal bioavailability. The metabolic profile for DCUK-OEt predicted a short half-life and needed improvement. No significant toxicities were noted, but given the indication (treatment of alcoholism) a number of additional studies on interactions with ethanol, and metabolism and toxicity in animals with organs compromised by chronic ethanol intake, were performed. The preclinical work is promising but just a beginning of the road. Clinical studies are complicated and expensive and the preclinical work needs to be sound to move a compound to the clinic. The author thanks Cecilia Borghese, Melissa Herman, Valentina Vengeliene and Olivier George for critical contributions to this work. Support: NIAAA (U44 AA24905).