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

优化用于治疗精神分裂症的 5-HT2c 铅配体

• 批准号: 8469720
• 负责人: Bryan L. Roth
• 金额: $ 79.84万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-05 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8469720
• 关键词: Adverse effects; Affect; Affinity; Agonist; Amygdaloid structure; Animal Model; Animal Testing; Animals; Antipsychotic Agents; Area; Behavior; Behavior assessment; Behavioral; Behavioral Assay; Behavioral Model; Binding; Biological Assay; Bipolar Disorder; Boxing; Cell Culture Techniques; Cell Nucleus; Characteristics; Chemicals; Clinic; Clinical; Clinical Trials; Cognition; Cognitive; Computer Simulation; Contracts; Delusions; Deterioration; Development; Disease; Dopamine; Drug Design; Drug abuse; Evaluation; Failure; Gender; Genetic; Genetic Models; Goals; HTR2A gene; Hallucinations; Hippocampus (Brain); Housing; Human; Hygiene; Hypertrophy; Hypothalamic structure; Impaired cognition; In Vitro; Incidence; Intuition; Knockout Mice; Lead; Life; Ligands; Medical; Mental Depression; Mental disorders; Metabolic; Molecular Target; Mus; National Institute of Mental Health; Neurobehavioral Manifestations; Nucleus Accumbens; Obesity; Obsessive-Compulsive Disorder; Outcome; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Population; Pre-Clinical Model; Preclinical Drug Evaluation; Process; Prosencephalon; Protein Isoforms; Psychotic Disorders; Psychotropic Drugs; Race; Refractory; Research; Schizophrenia; Schools; Serotonin; Serotonin Agonists; Serotonin Receptor 5-HT2B; Serotonin Receptor 5-HT2C; Solubility; Specificity; Staging; Structure of choroid plexus; Symptoms; Tardive Dyskinesia; Testing; Thinking; Ventral Tegmental Area; Vesicular stomatitis Indiana virus; Withdrawal; Work; addiction; atypical antipsychotic; base; design; drug candidate; improved; in vivo; innovation; interest; mRNA Expression; mouse model; neuropsychiatry; nigrostriatal system; novel; novel therapeutics; pre-clinical; programs; public health relevance; radioligand; receptor; research study; social; tool; treatment strategy

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.

描述（由申请人提供）：我们的最终目标是综合和表征新颖的5-HT2C 5-羟色胺激动剂，这些激动剂可能对治疗精神分裂症和相关疾病有用。我们的初步发现以及其他发现表明，5-HT2C激动剂在动物模型中有效地预测了针对精神分裂症的阳性和认知症状的功效。由于5-HT2C激动剂与当前典型和非典型抗精神病药的代谢和室内副作用的特征无关，因此5-HT2C激动剂会为精神分裂症和相关疾病提供新颖的治疗策略。为了实现这一总体目标，我们有三个具体的目标。目标1：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确定的有效的5-HT2C配体。将进行结构变化，以提高5-HT2C亚型的选择性，并避免任何5-HT2B瓣膜疗法相关的活性，同时还可以根据需要提高复合溶解度和ADMET参数，以实现临床前动物研究中所需的功效。 AIM 2：表征假定的5-HT2C的结合亲和力和功能活动 人和小鼠5-HT2C-INI，5-HT2C-NVN和5-HT2C-VSV受体 - 异构体的激动剂。我们还将通过放射性结合和功能测定法评估5-HT2A和5-HT2B受体活性来评估推定的5-HT2C激动剂的特异性。这些研究中出现的最佳化合物将经过大量的测定，以识别脱靶活动。目标3：评估特定目标1和2中确定的最佳5-HT2C配体 在一系列精神分裂症相关的行为测定中，以测试抗精神病性功效和可能的培养效应。行为研究将使用类似精神分裂症的行为的药理和遗传模型进行。 5-HT2C-敲除小鼠将用作对照。该提案的强度在于：（1）针对目前尚无批准药物的受体（即新型分子靶标）； （2）5-HT2C激动剂可能具有精神分裂症以外的临床适应症，包括躁郁症，抑郁，肥胖和药物滥用（即许多潜在的临床指示）； （3）关于精神分裂症，两种不同的5-HT2C激动剂已经显示出在动物模型中的功效，可预测阳性和认知样精神分裂症症状的功效。由于在精神分裂症中很难治疗认知症状，因此5-HT2C化合物可能代表一种新颖的治疗策略。 （4）最后，5-HT2C激动剂不仅可能没有与当前药物相关的代谢AD Motoric副作用，而且从代谢角度来看也可能是有益的。