In alcohol-dependent persons, cessation of drinking leads to craving for alcohol and symptoms of alcohol withdrawal syndrome (AWS). These symptoms vary in type, intensity, timing and frequency, and include tremor, anxiety, autonomic hyperactivity (sweating, increased blood pressure, tachycardia), hallucinations, seizures and delirium tremens. Although sometimes unrecognized, AWS can be life threatening and thus requires active, pharmacological treatment. Alcohol withdrawal syndrome is caused in part by increased expression of neuronal voltage-gated L- and N-type calcium channels. Studies by the P.I. and his collaborators show that farnesol, a 15-carbon isoprenol with specific voltage-gated L- and N-type calcium channel blocker activity suppresses withdrawal seizures in alcohol-dependent mice. This finding suggests that farnesol or structurally related compounds may prove useful in the treatment of AWS patients. Our specific goal is to characterize the anti-AWS activity of a series of farnesol analogues, identified using their activity on vascular L-type calcium channels and their putative metabolism by farnesol-specific intracellular enzymes. These compounds will be synthesized in quantities appropriate for in vivo experiments, or obtained from commercial source, and tested for activity on withdrawal seizures in alcohol-dependent mice. A parallel assessment of the compounds' activity on neuronal Ca2+ channels is also proposed to establish structure-activity relationship. Technological innovation: novel class of drugs with specific activity on alcohol withdrawal seizures. Potential commercialization: This research will provide the foundation for Phase II evaluation of the most active farnesol analogue in the treatment of alcohol withdrawal syndrome in alcoholic patients.
