Optimizing Lead 5-HT2c Ligands for Use in the Treatment of Schizophrenia

描述（由申请人提供）：我们的最终目标是合成和表征可用于治疗精神分裂症和相关病症的新型5-HT 2c血清素激动剂。我们的初步研究结果以及其他研究结果表明，5-HT 2C激动剂在预测对精神分裂症阳性和认知症状有效的动物模型中是有效的。由于5-HT 2C激动剂与目前典型和非典型抗精神病药物的代谢和运动副作用特征无关，因此5-HT 2C激动剂将为精神分裂症和相关病症提供新的治疗策略。为了实现这一总体目标，我们有三个具体目标。目标1：为了进一步扩展和改进我们已经使用合理的药物设计原理和化学直觉鉴定的有效5-HT 2c配体。将进行结构改变以增强5-HT 2c亚型选择性并避免任何5-HT 2B瓣膜病相关活性，同时还根据需要改善化合物溶解度和ADMET参数，以在临床前动物研究中实现所需疗效。目的2：表征推定的5-HT 2c的结合亲和力和功能活性 人和小鼠5-HT 2c-INI、5-HT 2c-NVN和5-HT 2c-VSV受体亚型的激动剂。我们还将通过放射性配体结合和功能测定评估5-HT 2A和5-HT 2B受体活性来评价推定的5-HT 2c激动剂的特异性。这些研究中出现的最佳化合物将进行一系列大型试验，以鉴定脱靶活性。目的3：评价特定目的1和2中鉴定的最佳5-HT 2c配体 在一系列精神分裂症相关的行为分析中，以测试抗精神病药物的疗效和可能的促认知作用。行为研究将使用精神分裂症样行为的药理学和遗传模型进行; 5-HT 2C敲除小鼠将作为对照。这一建议的优势在于：（1）针对目前没有批准药物的受体（即一种新的分子靶点）;（2）5-HT 2C激动剂可能具有精神分裂症以外的临床适应症，包括双相情感障碍、抑郁症、肥胖症和药物滥用（即，许多潜在的临床适应症）;（3）关于精神分裂症，两种不同的5-HT 2C激动剂已经在动物模型中显示出对阳性和认知样精神分裂症症状的功效的预测功效。由于精神分裂症的认知症状很难治疗，5-HT 2C化合物可能代表一种新的治疗策略;（4）最后，5-HT 2C激动剂可能不仅没有与当前药物相关的代谢性运动副作用，而且从代谢角度来看也可能是有益的。

DESCRIPTION (provided by applicant): Our ultimate goal is to synthesize and characterize novel 5-HT2c serotonin agonists that may be useful for treating schizophrenia and related disorders. Our preliminary findings, as well as those of others, indicate that 5-HT2C agonists are effective in animal models predictive of efficacy against the positive and cognitive symptoms of schizophrenia. Because 5-HT2C agonists are not associated with the metabolic and motoric side- effects characteristic of current typical and atypical antipsychotic drugs, 5-HT2C agonists would afford novel treatment strategies for schizophrenia and related disorders. To achieve this overall goal we have three specific aims. Aim 1: To further expand and improve upon the potent 5-HT2c ligands that we have already identified using rational drug design principles and chemical intuition. Structural alterations will be made to enhance 5-HT2c subtype selectivity and to avoid any 5-HT2B valvuopathic-associated activity, while also improving upon compound solubility and ADMET parameters as needed to achieve the desired efficacy in preclinical animal studies. Aim 2: Characterize binding affinities and functional activities of putative 5-HT2c agonists for the human and mouse 5-HT2c-INI, 5-HT2c-NVN and 5-HT2c-VSV receptor-isoforms. We will also evaluate specificity of putative 5-HT2c agonists by assessing 5-HT2A and 5-HT2B receptor activities by radioligand binding and functional assays. The best compounds emerging from these studies will be subjected to a large battery of assays for identification of off-target activity. Aim 3: To evaluate the best 5-HT2c ligands identified in Specific Aims 1 and 2 in a battery of schizophrenia- related behavioral assays to test for antipsychotic efficacy and possible pro-cognitive effects. The behavioral studies will be conducted with pharmacological and genetic models of schizophrenia-like behaviors; 5-HT2C- knockout mice will serve as controls. The strength of this proposal lies in: (1) Targeting a receptor for which there are no currently approved medications (i.e. a novel molecular target); (2) 5-HT2C agonists are likely to have clinical indications beyond schizophrenia including bipolar disorder, depression, obesity, and drug abuse (i.e. many potential clinical indications); (3) With respect to schizophrenia, two different 5-HT2C agonists have already shown efficacy in animal models predictive of efficacy for positive- and cognitive-like schizophrenia symptoms. Since cognitive symptoms are very difficult to treat in schizophrenia, the 5-HT2C compounds may represent a novel treatment strategy; (4) Finally, it is likely that 5-HT2C agonists will not only be devoid of the metabolic ad motoric side- effects associated with current medications but may also be beneficial from a metabolic perspective.