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

描述(申请人提供)：我们的最终目标是合成和表征可能用于治疗精神分裂症和相关疾病的新型5-HT2C 5-羟色胺激动剂。我们和其他人的初步发现表明，5-HT2C激动剂在动物模型中是有效的，可以预测对精神分裂症的阳性和认知症状的疗效。由于5-HT2C激动剂与当前典型和非典型抗精神病药物所特有的代谢和运动副作用无关，5-HT2C激动剂将为精神分裂症和相关疾病提供新的治疗策略。为了实现这一总体目标，我们有三个具体目标。目的1：利用合理的药物设计原则和化学直觉，进一步扩展和改进我们已经确定的有效的5-HT2C配体。将进行结构改变，以提高5-HT2C亚型的选择性，避免任何与5-HT2B瓣膜病变相关的活性，同时还将根据需要改善化合物的溶解度和适形参数，以在临床前动物研究中达到预期的效果。目的2：表征5-HT2C的结合亲和力和功能活性 人和小鼠5-HT2C-INI，5-HT2C-NVN和5-HT2C-VSV受体-异构体的激动剂。我们还将通过放射配基结合和功能分析评估5-HT2A和5-HT2B受体的活性，以评估可能的5-HT2C激动剂的特异性。从这些研究中发现的最好的化合物将接受大量的测试，以确定脱离目标的活性。目的3：评价特定目标1和2中确定的最佳5-HT2C配体 在一系列与精神分裂症相关的行为分析中，测试抗精神病药物的疗效和可能的促进认知的效果。行为学研究将使用类似精神分裂症行为的药理学和遗传学模型进行；5-HT2C基因敲除小鼠将作为对照。这项建议的力量在于：(1)针对目前尚无药物治疗的受体(即新的分子靶点)；(2)5-HT2C激动剂很可能在精神分裂症以外的临床症状中具有疗效，包括双相情感障碍、抑郁、肥胖和药物滥用(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-HT2C激动剂已经在动物模型中显示出疗效，预测对阳性和认知样精神分裂症症状的疗效。由于精神分裂症的认知症状很难治疗，5-HT2C化合物可能代表着一种新的治疗策略；(4)最后，5-HT2C激动剂很可能不仅没有与目前药物相关的代谢和运动副作用，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.