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

描述（由申请人提供）：这项研究是为了推进新型国际专利苯氨基四氢萘（PAT）类似物作为功能选择性血清素5 HT 2受体为基础的药物开发候选药物，用于治疗苯丙胺和甲基苯丙胺成瘾以及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/反向激动减弱啮齿动物的精神兴奋剂作用。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受体的共同拮抗作用有助于与抗精神病药物相关的体重增加。PAT独特地显示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安非他明/甲基安非他明成瘾和诱导的精神病的行为模型中的治疗活性，在啮齿动物中外周给药后没有明显的不良反应（包括体重增加）。这种新的5 HT 2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一个进步，这些方法已被证明是药物成瘾药物治疗的次优方法，而多价或二价5-羟色胺5 HT 2化合物造成了许多ADMET限制。基于初步的体内结构-活性关系，我们将优化PAT分子支架的活性，通过合成至少50种新的单一对映体PAT，对（C2）胺，（C4）侧基苯基和四氢萘基部分进行修饰，以减弱苯丙胺/甲基苯丙胺成瘾。体外药理学研究包括测定PAT 5 HT 2A、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 GPCR的建模基于与人肾上腺素能22 GPCR结构的同源性，这是对使用与牛视紫红质GPCR同源性的先前模型的创新性进步。具有5 HT 2A/2B反向激动作用的强效和有效的PAT 5 HT 2C激动剂被推进临床前研究，以评估体内减轻苯丙胺和甲基苯丙胺成瘾和药物诱导的精神障碍的药效。进行PAT的系统行为分析以提供关于药代动力学变量、关于5 HT 2A反向激动与5 HT 2C激动的5 HT 2系统中的功能活性以及药物诱导的精神障碍的减弱的信息。研究包括使用安非他明和甲基安非他明药物辨别和自我给药程序来验证5 HT 2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的强化作用的衰减，这些行为程序旨在模拟成瘾样行为表型的关键方面。 公共卫生相关性：尽管8%的美国人非法使用这些精神兴奋剂，但FDA尚未批准治疗苯丙胺/甲基苯丙胺使用障碍的药物。该申请解决了开发用于苯丙胺和甲基苯丙胺成瘾和诱导的精神障碍的新药的迫切需要。

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.