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。每年因肥胖和超重导致的医疗支出约为1170亿美元。由于现有药物疗效一般，副作用大，迫切需要发现有效的药物来治疗这种疾病。抗肥胖药物的潜在目标是大麻素（CB1）受体。在该提案的I期，我们的重点将放在我们的新型THC/anandamide模板的结构优化上，以发现一种或多种CB1受体拮抗剂。为了区分激动剂和拮抗剂的活性，将评估与CB1受体有效结合的类似物刺激[35S]GTPgS结合的能力。我们的具体目标是发现并选择该系列中表现出体内活性的抑制食欲的小鼠模型中最好的类似物。如果是上述情况

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.