Novel THC/Anandamide Hybrids as Appetite Suppressants

肥胖症已经达到流行的程度，每年约有30万人死于与肥胖相关的疾病。每年因肥胖和超重而导致的医疗支出约为1170亿美元。目前迫切需要寻找有效的药物来治疗这种疾病，因为现有的药物疗效不大，副作用也很大。抗肥胖药物的一个潜在目标是大麻素(CB1)受体。在这项建议的第一阶段，我们的重点将放在我们的新型THC/anandamide模板的结构优化上，以发现一个或多个CB1受体拮抗剂。为了区分激动剂和拮抗剂的活性，有效地与CB1受体结合的类似物将被评估它们刺激[35S]GTPgS结合的能力。我们的具体目标是在这个系列中发现和选择在小鼠模型中表现出体内活性的最佳类似物来抑制食欲。如果出现上述情况 目标在第一阶段完成后，我们将在第二阶段有进一步开发的候选药物。这项建议的长期目标是开发一种既安全又有效的新型抗肥胖药物。

Obesity has reached epidemic proportions and in a year about 300,000 people die of obesity-related diseases. Annual medical spending due to obesity and overweight is about $117 billion. There is an urgent need to discover effective drugs to treat this disease since existing drugs have modest efficacy and significant side effects. A potentially promising target for anti-obesity drugs is the cannabinoid (CB1) receptor. In Phase I of this proposal our focus will be on the structural optimization of our novel THC/anandamide template to discover one or more CB1 receptor antagonists. In order to distinguish between agonist and antagonist activity, analogs that bind effectively to the CB1 receptor, will be evaluated for their ability to stimulate [35S]GTPgS binding. Our specific objective is to discover and select the best analogs in this series that manifest in vivo activity in a mouse model for appetite suppression. If the above objective is accomplished in Phase I, we will have a drug candidate for further development in Phase II. The long-term objective of this proposal is to develop a novel anti-obesity drug that is both safe and effective.