Farnesol Analogues as Novel Treatment of Alcoholism

描述（由申请人提供）：在酒精依赖者中，停止饮酒会导致对酒精的渴望和酒精戒断综合征（AWS）的症状。这些症状在类型、强度、时间和频率上各不相同，包括震颤、焦虑、自主神经功能亢进（出汗、血压升高、心动过速）、幻觉、癫痫发作和谵妄。虽然有时无法识别，AWS可能危及生命，因此需要积极的药物治疗。 酒精戒断综合征部分是由神经元电压门控L型和N型钙通道表达增加引起的。P.I.的研究和他的合作者表明，法尼醇，一种具有特定电压门控L-和N-型钙通道阻滞剂活性的15-碳异戊二烯醇，抑制酒精依赖小鼠的戒断发作。这一发现表明，法尼醇或结构相关的化合物可能被证明是有用的AWS患者的治疗。 我们的具体目标是表征一系列法尼醇类似物的抗AWS活性，使用它们对血管L型钙通道的活性和它们通过法尼醇特异性细胞内酶的推定代谢来鉴定。这些化合物将以适合于体内实验的量合成，或从商业来源获得，并在酒精依赖性小鼠中测试对戒断性癫痫发作的活性。还提出了平行评估化合物对神经元Ca 2+通道的活性，以建立构效关系。 技术创新：新型药物对酒精戒断发作具有特异性活性。 潜在商业化：这项研究将为最有效的法尼醇类似物治疗酒精戒断综合征的II期评估提供基础。

DESCRIPTION (provided by applicant): 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.