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

描述（由申请人提供）：本研究旨在推进具有国际专利的新型苯胺四分灵（phenylaminotetralin， PAT）类似物作为基于5 -羟色胺5HT2受体的功能选择性药物开发候选药物，用于治疗安非他命和甲基苯丙胺成瘾以及药物性精神障碍。脑5HT2C受体的激活或5HT2A受体的拮抗/逆激动作用减弱了啮齿动物的精神兴奋作用。除PATs外，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，激活脑5HT2A受体产生拟精神作用，激活外周5HT2B受体产生心瓣膜病变和肺动脉高压。相反，5HTC和5HT2A受体的共拮抗作用与抗精神病药物相关的体重增加有关。PATs独特地表现出5HT2C受体的激动作用，同时具有5HT2A和5HT2B的反激动作用——这种5HT2功能选择性在体内转化为安非他明/甲基苯丙胺成瘾和诱导精神病的行为模型的治疗活性，在啮齿动物的外周给药后没有明显的副作用（包括体重增加）。这种新颖的5HT2功能选择性单分子方法是针对多巴胺神经元蛋白的一种进步，多巴胺神经元蛋白已被证明是药物成瘾药物治疗的次优方法，而多价或双价5 -羟色胺5HT2化合物具有许多ADMET限制。基于初步的体内结构-活性关系，我们将通过合成至少50个新的单对映体PAT来优化PAT分子支架的活性，以减轻安非他命/甲基苯丙胺成瘾，这些分子支架对（C2）胺、（C4）悬挂苯基和四氢萘基进行修饰。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）。利用5HT2受体分子模型进行PAT对接研究，将表征PAT-5HT2分子间的相互作用，从而设计更多的靶分子。5HT2 GPCR的建模是基于与人类肾上腺素能22 GPCR结构的同源性，这是先前使用与牛视紫红质GPCR同源性的模型的创新进步。高效且具有5HT2A/2B逆激动作用的PAT 5HT2C激动剂被推广到临床前研究，以评估其在体内减轻安非他明和甲基苯丙胺成瘾及药物性精神障碍的药物治疗效果。对PATs进行了系统的行为分析，以提供有关5HT2A与5HT2C拮抗作用的药代动力学变量、5HT2系统的功能活性以及药物性精神障碍的衰减的信息。研究包括使用安非他明和甲基苯丙胺药物鉴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效应的衰减，这些行为程序旨在模拟成瘾样行为表型的关键方面。

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.