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: 8715749
• 负责人: Raymond G. Booth
• 金额: $ 30.98万
• 依托单位: NORTHEASTERN UNIVERSITY
• 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 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8715749
• 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; receptor; scaffold; single molecule; stimulant abuse; success

ABSTRACT: 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 ¿2 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.

摘要：本研究旨在推进新型国际专利苯氨基四氢化萘（PAT）类似物， 基于功能选择性5-羟色胺5 HT 2受体的药物开发候选物，用于治疗安非他明和 甲基苯丙胺成瘾和药物引起的精神障碍。脑5 HT 2C受体的激活或 5 HT 2A受体的拮抗/反向激动作用减弱啮齿动物中的精神兴奋作用。与 除了PAT之外，文献中报道的激活5 HT 2C受体的所有化合物也激活5 HT 2A 和/或5 HT 2B受体-不幸的是，脑5 HT 2A受体的激活产生拟精神病效应 外周5 HT 2B受体的激活产生心脏瓣膜病和肺动脉高压。 相反，5 HTC和5 HT 2A受体的共拮抗作用有助于与以下相关的体重增加： 抗精神病药物PAT独特地表现出5 HT 2C受体激动作用，同时具有5 HT 2A和 5 HT 2B反向激动作用-这种5 HT 2功能选择性在体内转化为行为学中的治疗活性。 苯丙胺/甲基苯丙胺成瘾和诱发精神病模型，无明显不良反应 （包括体重增加）。这种新型的5 HT 2功能选择性单 分子方法比靶向多巴胺神经元蛋白的方法更先进，这些方法已被证明 对于药物成瘾药物治疗是次优的，而多价或二价5-羟色胺5 HT 2化合物 ADMET有很多局限性。基于初步的体内构效关系，我们将 优化PAT分子支架的活性以减弱苯丙胺/甲基苯丙胺成瘾， 合成至少50种对（C2）胺、（C4）侧基进行修饰的新的单一对映体PAT 苯基和四氢萘基部分。体外药理学研究包括PAT 5 HT 2A的测定， 2B和2C亲和力（Ki）和功能（EC 50/IC 50）。使用5 HT 2受体分子模型的PAT对接研究 将表征PAT-5 HT 2分子相互作用，用于设计其他靶分子。5 HT 2模型 GPCR基于与人肾上腺素能GPCR结构的同源性，这是一项创新性进展， 使用与牛视紫红质GPCR同源的先前模型。强效PAT 5 HT 2C 具有5 HT 2A/2B反向激动作用的激动剂被推进临床前研究以评估药效学 减轻安非他明和甲基安非他明成瘾和药物诱导精神病的体内功效 紊乱对PAT进行系统的行为分析，以提供药代动力学信息 变量，5 HT 2系统中关于5 HT 2A反向激动相对于5 HT 2C激动的功能活性，和 减轻药物引起的精神障碍。研究包括使用安非他明和甲基安非他明 药物鉴别和自我给药程序，以验证5 HT 2受体系统作为靶点， 兴奋剂药物疗法，并评估这些兴奋剂在各种 行为程序的设计，以模仿成瘾样行为表型的关键方面。

项目成果

Synthesis of novel 5-substituted-2-aminotetralin analogs: 5-HT1A and 5-HT7 G protein-coupled receptor affinity, 3D-QSAR and molecular modeling.

新型 5-取代-2-氨基四氢化萘类似物的合成：5-HT1A 和 5-HT7 G 蛋白偶联受体亲和力、3D-QSAR 和分子建模。

• DOI: 10.1016/j.bmc.2019.115262
• 发表时间: 2020
• 期刊: Bioorganic & medicinal chemistry
• 影响因子: 3.5
• 作者: Perry,CharlesK;Casey,AustenB;Felsing,DanielE;Vemula,Rajender;Zaka,Mehreen;Herrington,NoahB;Cui,Meng;Kellogg,GlenE;Canal,ClintonE;Booth,RaymondG
• 通讯作者: Booth,RaymondG