Novel THC/Anandamide Hybrids as Appetite Suppressants

肥胖已达到流行病的程度，每年约有30万人死于与肥胖有关的疾病。每年因肥胖和超重造成的医疗支出约为1170亿美元。目前迫切需要发现有效的药物来治疗这种疾病，因为现有的药物具有适度的疗效和显著的副作用。抗肥胖药物的一个潜在的有希望的靶点是大麻素（CB 1）受体。在该提案的第一阶段，我们的重点将是我们的新型THC/大麻素模板的结构优化，以发现一种或多种CB 1受体拮抗剂。为了区分激动剂和拮抗剂活性，将评价有效结合CB 1受体的类似物刺激[35 S]GTPgS结合的能力。我们的具体目标是发现和选择该系列中表现出食欲抑制小鼠模型体内活性的最佳类似物。如果上述 在第一阶段完成目标后，我们将有一种候选药物用于第二阶段的进一步开发。该提案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.