Novel Functionally-Selective Serotonin 5HT2 Drugs for Amphetamines Abuse/Disorder

用于治疗安非他明滥用/疾病的新型功能选择性血清素 5HT2 药物

• 批准号: 8144930
• 负责人: Raymond G. Booth
• 金额: $ 35.04万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-30 至 2012-09-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8144930
• 关键词: Address; Adrenergic Agents; Adverse effects; Affinity; Agonist; American; Amines; Amphetamine Abuse; Amphetamine Addiction; Amphetamines; Antipsychotic Agents; Attenuated; Behavior; Behavioral; Behavioral Mechanisms; Behavioral Model; Binding; Binge Eating; Biological Assay; Brain; Cardiac; Cattle; Cells; Cocaine; Data; Development; Dimethylamines; Disease; Docking; Dopamine; Drug Kinetics; Eating Disorders; Effectiveness; FDA approved; Family; G Protein-Coupled Receptor Genes; Goals; Histamine; Human; Human Cloning; In Vitro; Inhibitory Concentration 50; Intake; International; Legal patent; Ligands; Literature; Locomotion; Medicine; Methamphetamine; Methamphetamine dependence; Methods; Modeling; Modification; Molecular; Molecular Models; Motor Activity; Neurons; Obesity; Outcome; Peripheral; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Probability; Procedures; Proteins; Psychostimulant dependence; Psychotic Disorders; Publishing; Pulmonary Hypertension; Rattus; Relapse; Relative (related person); Reporting; Research; Rhodopsin; Rodent; Rodent Model; Schizophrenia; Secure; Self Administration; Serotonin; Structure; Structure-Activity Relationship; System; Therapeutic; Therapeutic Agents; Therapeutic Uses; Translating; United States National Institutes of Health; Weight Gain; addiction; adrenergic; analog; attenuation; base; design; dimethylamine; drug addiction pharmacotherapy; drug development; drug discrimination; enantiomer; improved; in vivo; innovation; interest; methamphetamine abuse; molecular modeling; neuropsychiatry; novel; preclinical study; psychostimulant; public health relevance; receptor; scaffold; single molecule; stimulant abuse; success

DESCRIPTION (provided by applicant): This research is to advance novel internationally-patented phenylaminotetralin (PAT) analogs as functionally-selective serotonin 5HT2 receptor-based drug development candidates to treat amphetamine and methamphetamine addiction and drug-induced psychotic disorders. Activation of brain 5HT2C receptors or antagonism/inverse agonism of 5HT2A receptors attenuates psychostimulant effects in rodents. With the exception of PATs, all compounds reported in the literature that activate 5HT2C receptors also activate 5HT2A and/or 5HT2B receptors-unfortunately, activation of brain 5HT2A receptors produces psychotomimetic effects and activation of peripheral 5HT2B receptors produces cardiac valvulopathy and pulmonary hypertension. Conversely, co-antagonism of 5HTC and 5HT2A receptors contributes to weight-gain associated with antipsychotic drugs. PATs uniquely demonstrate 5HT2C receptor agonism simultaneously with 5HT2A and 5HT2B inverse agonism-this 5HT2 functional selectivity translates in vivo to therapeutic activity in behavioral models of amphetamine/methamphetamine addiction and induced psychoses, with no overt adverse effects (including, weight-gain) after peripheral administration in rodents. This novel 5HT2 functionally-selective single molecule approach is an advance over approaches targeting dopamine neuronal proteins that have proven to be sub-optimal for drug addiction pharmacotherapy, while multiple or bi-valent serotonin 5HT2 compounds pose numerous ADMET limitations. Based on a preliminary in vivo structure-activity relationship, we will optimize the PAT molecular scaffold for activity to attenuate amphetamine/methamphetamine addiction by synthesis of at least 50 novel single-enantiomer PATs with modifications to the (C2) amine, (C4) pendant phenyl, and tetrahydronaphthyl moieties. In vitro pharmacology studies include determination of PAT 5HT2A, 2B, and 2C affinity (Ki) and function (EC50/IC50). PAT docking studies using 5HT2 receptor molecular models will characterize PAT-5HT2 molecular interactions for design of additional target molecules. Modeling of 5HT2 GPCRs is based on homology to the structure of the human adrenergic 22 GPCR, an innovative advance over previous models that used homology to the bovine rhodopsin GPCR. Potent and efficacious PAT 5HT2C agonists with 5HT2A/2B inverse agonism are promoted to preclinical studies to evaluate pharmacotherapeutic efficacy in vivo to attenuate amphetamine and methamphetamine addiction and drug-induced psychotic disorders. A systematic behavioral analysis of PATs is undertaken to provide information on pharmacokinetic variables, functional activity in the 5HT2 system regarding 5HT2A inverse agonism vs. 5HT2C agonism, and attenuation of drug-induced psychotic disorders. Studies include using amphetamine and methamphetamine drug discrimination and self-administration procedures to validate 5HT2 receptor systems as targets for stimulant pharmacotherapies and assess attenuation of the reinforcing effects of these stimulants in a variety of behavioral procedures designed to mimic critical aspects of an addiction-like behavioral phenotype. PUBLIC HEALTH RELEVANCE: There are no FDA approved medications for amphetamine/methamphetamine use disorders despite illicit use of these psychostimulants by 8% of Americans. This application addresses the critical need to develop novel medicines for amphetamine and methamphetamine addiction and induced psychotic disorders.

描述(申请人提供)：这项研究是为了推进新的国际专利的苯氨基四氢呋喃(PAT)类似物，作为基于5HT2受体的功能性选择性药物开发候选药物，用于治疗苯丙胺和甲基苯丙胺成瘾和药物引起的精神障碍。脑内5HT2C受体的激活或5HT2A受体的拮抗/反向兴奋可减弱啮齿动物的精神刺激效应。除了PATS，文献中报道的所有激活5HT2C受体的化合物也激活5HT2a和/或5HT2b受体-不幸的是，激活大脑5HT2a受体会产生拟精神病效应，激活外周5HT2b受体会产生心脏瓣膜病和肺动脉高压。相反，5HTC和5HT2A受体的共同拮抗会导致与抗精神病药物相关的体重增加。PATS独一无二地同时展示了5HT2C受体激动性和5HT2a和5HT2b反向激动性--这种5HT2功能选择性在安非他明/甲基苯丙胺成瘾和诱发精神病的行为模型中在体内转化为治疗活性，在啮齿动物外周给药后没有明显的不良反应(包括体重增加)。这种新的5HT2功能选择性单分子方法是针对多巴胺神经元蛋白的方法的进步，后者已被证明是药物成瘾药物治疗的次佳方法，而多价或二价5-羟色胺5HT2化合物构成了许多ADMET限制。基于初步的体内构效关系，我们将通过对(C2)胺、(C4)侧苯基和四氢萘基部分进行修饰，合成至少50个新的单一对映体PATs，以优化PAT分子支架的活性，以减轻苯丙胺/甲基苯胺成瘾的活性。体外药理学研究包括测定PAT 5HT2A、2B和2C的亲和力(Ki)和功能(EC50/IC50)。使用5HT2受体分子模型的PAT对接研究将表征PAT-5HT2分子相互作用，以设计更多的目标分子。5HT2 GPCRs的建模是基于与人类肾上腺素能22GPCRs的结构的同源性，比以前使用与牛视紫质GPCR同源性的模型是一个创新的进步。具有5HT2A/2B反向激动剂的有效有效的PAT 5HT2C激动剂被推广到临床前研究，以评估体内对苯丙胺和甲基苯丙胺成瘾以及药物所致精神障碍的药物治疗效果。对PATS进行了系统的行为学分析，以提供关于药代动力学变量、5HT2系统中关于5HT2A反向激动剂与5HT2C激动剂的功能活性以及药物引起的精神障碍的缓解的信息。研究包括使用苯丙胺和甲基苯丙胺药物识别和自我给药程序来验证5HT2受体系统作为兴奋剂药物治疗的靶点，并评估这些兴奋剂在各种行为程序中增强作用的减弱，这些程序旨在模拟成瘾样行为表型的关键方面。 公共卫生相关性：尽管8%的美国人非法使用安非他明/甲基苯丙胺，但目前还没有FDA批准的治疗安非他明/甲基苯丙胺使用障碍的药物。这项申请解决了开发治疗苯丙胺和甲基苯丙胺成瘾和诱发精神障碍的新药物的迫切需要。