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

摘要：本研究旨在将国际专利的新型苯氨基四氢呋喃(PAT)类似物作为 基于功能性选择性5-羟色胺5-HT2受体的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/反向激动剂可减弱啮齿动物的精神刺激效应。与 除PAT外，文献中报道的所有能激活5HT2C受体的化合物也能激活5HT2a 和/或5HT2b受体-不幸的是，大脑5HT2a受体的激活会产生精神分裂效应 而外周5HT2b受体的激活会导致心脏瓣膜病和肺动脉高压。 相反，5HTC和5HT2A受体的共同拮抗有助于体重增加，与 抗精神病药物。PATS独一无二地与5HT2A和5HT2C受体同时显示5HT2C受体激动性 5HT2b反向激动剂--这种5HT2功能选择性在体内转化为行为上的治疗活性 无明显不良反应的苯丙胺/甲基苯丙胺成瘾和诱发精神病模型 (包括体重增加)在啮齿动物外周给药后。这种新型的5HT2功能选择性单体 分子方法是相对于靶向多巴胺神经元蛋白的方法的进步，后者已被证明 药物成瘾药物治疗次佳，而多价或二价5-羟色胺5HT2化合物 造成了许多ADMET限制。基于初步的体内构效关系，我们将 优化PAT分子支架减轻苯丙胺/甲基苯丙胺成瘾的活性 至少50个新型(C2)胺、(C4)侧基修饰的单对映体PATS的合成 苯基和四氢萘基。体外药理研究包括测定PAT 5HT2A， 2B和2C亲和力(Ki)和功能(EC50/IC50)。基于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的建模 GPCRs的基础是与人类肾上腺素能GPCRs的结构同源，这是对 以前的模型使用了与牛视紫红质GPCR同源的基因。强而有效的PAT 5HT2C 具有5HT2A/2B反向激动剂的激动剂被提升到临床前研究以评估药物治疗 减轻苯丙胺和甲基苯丙胺成瘾及药物所致精神病患者的体内疗效 精神错乱。对PATS进行了系统的行为分析，以提供药代动力学信息。 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 减轻药物引起的精神障碍。研究包括使用安非他明和甲基苯丙胺 验证5HT2受体系统作为靶点的药物识别和自我给药程序 刺激性药物治疗和评估这些刺激剂在各种情况下的增强作用的减弱 旨在模仿成瘾样行为表型的关键方面的行为程序。

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.