Smith Brian M, Thomsen William J, Grottick Andrew J
Arena Pharmaceuticals Research & Development, San Diego, CA 92121, USA.
Expert Opin Investig Drugs. 2006 Mar;15(3):257-66. doi: 10.1517/13543784.15.3.257.
Activation of central 5-HT2C receptors as a strategy for appetite suppression and weight control is supported by animal pharmacology and human clinical studies. Considerable evidence comes from the weight-loss effects of fenfluramine, a non-selective 5-HT2C agonist. Advances in molecular pharmacology have led to an understanding of the effects of 5-HT2C receptor activation on food intake and satiety, in addition to providing insight into the causes of cardiac valvular insufficiency and pulmonary hypertension associated with the use of fenfluramine. However, clinically validated animal models of drug-induced disease and knowledge of the molecular mechanisms of these safety issues is lacking. For this reason, the development of selective 5-HT2C agonists for the treatment of obesity has remained a challenge.
动物药理学和人体临床研究均支持激活中枢5-HT2C受体作为抑制食欲和控制体重的策略。大量证据来自非选择性5-HT2C激动剂芬氟拉明的减肥效果。分子药理学的进展不仅使人们了解了5-HT2C受体激活对食物摄入和饱腹感的影响，还深入了解了与使用芬氟拉明相关的心脏瓣膜功能不全和肺动脉高压的病因。然而，缺乏经过临床验证的药物诱导疾病动物模型以及对这些安全问题分子机制的了解。因此，开发用于治疗肥胖症的选择性5-HT2C激动剂仍然是一项挑战。
