Novel 5HT2C Agonist Drugs with 5HT2A Antagonist Activity for Cocaine Addiction

描述（由申请人提供）：目前没有可卡因滥用的药物治疗。本申请直接响应RFA-DA-07-006，解决了这一公共卫生危机。本申请旨在开发具有5 HT 2A/5 HT 2B受体拮抗剂活性的新型5-羟色胺5 HT 2C受体激动剂药物，以减轻可卡因使用和依赖的行为和神经化学作用。临床前数据表明，脑5 HT 2C受体的激活减弱了可卡因的强化作用，而可卡因的辨别刺激和恢复作用对5 HT 2C激活和5 HT 2A阻断的衰减敏感。 同时，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。目前，没有报道不激活5 HT 2A和/或5 HT 2B受体的5 HT 2C受体激动剂。然而，本文报道的初步数据表明，我们实验室合成的分子（1 R，3S）-（-）-trans-1-phenyl-3-dimethylamino-1，2，3，4-tetrahydronaphthalene（PAT）是人5 HT 2C受体的全效激动剂，以及5 HT 2A和5 HT 2B受体的拮抗剂。这种对多种5-羟色胺受体的双重活性（激活/阻断）是（-）-trans-PAT所独有的，并被假设为可卡因成瘾提供药理学治疗而无心脏毒性。创新方法包括靶向合成新型PAT型立体探针，以绘制用于选择性激活5 HT 2C受体的3D分子决定簇，以及复杂的自我给药程序，以确定对PAT类似物调节敏感的可卡因滥用相关效应。微透析与毛细管电泳/激光诱导荧光将允许15秒的时间分辨率可卡因自我管理大鼠的神经化学变化，以确定PAT治疗效果的神经化学机制。具体目标是：（1）PAT类似物合成和定量结构-活性关系建模，（2）PAT 5 HT 2亲和力和功能活性的体外表征，（3）评价PAT对可卡因滥用相关作用的调节的体内行为药理学研究，以及（4）PAT-可卡因神经化学相互作用的体内分析。这项研究是由一个多学科的研究人员团队进行的，用于临床前开发新的化合物，这些化合物可能会转化为可卡因滥用的创新药理干预。

DESCRIPTION (provided by applicant): There is currently no pharmacotherapy for cocaine abuse. This public health crisis is addressed in this application that is directly responsive to RFA-DA-07-006. This application is for development of novel serotonin 5HT2C receptor agonist drugs with 5HT2A/5HT2B receptor antagonist activity to attenuate the behavioral and neurochemical effects of cocaine use and dependence. Preclinical data indicate activation of brain 5HT2C receptors attenuates the reinforcing effects of cocaine, whereas discriminative stimulus and reinstating effects of cocaine are sensitive to attenuation by both 5HT2C activation and 5HT2A blockade. Meanwhile, activation of brain 5HT2A receptors produces psychotomimetic effects and activation of peripheral 5HT2B receptors produces cardiac valvulopathy and pulmonary hypertension. Currently, there is no 5HT2C receptor agonist reported that does not also activate 5HT2A and/or 5HT2B receptors. Preliminary Data reported here, however, demonstrate that a molecule synthesized in our lab, (1R,3S)-(-)-trans-1-phenyl-3-dimethylamino-1,2,3,4-tetrahydronaphthalene (PAT), is a full-efficacy agonist at human 5HT2C receptors, plus, an antagonist at 5HT2A and 5HT2B receptors. This dual activity (activation/blockade) at multiple serotonin receptors is unique to (-)-trans-PAT and is hypothesized to provide pharmacological treatment for cocaine addiction without cardiotoxicity. Innovative approaches include targeted syntheses of novel PAT-type stereoprobes to map 3D molecular determinants for selective activation of 5HT2C receptors and sophisticated self-administration procedures to identify cocaine's abuse-related effects that are sensitive to modulation by PAT analogs. Microdialysis with capillary electrophoresis/ laser-induced fluorescence will allow 15-sec temporal resolution of neurochemical changes in cocaine self-administering rats to identify neurochemical mechanisms of PAT therapeutic effects. The Specific Aims are: (1) PAT analog syntheses and quantitative structure-activity relationship modeling, (2) in vitro characterization of PAT 5HT2 affinity and functional activity, (3) in vivo behavioral pharmacology studies to evaluate PAT modulation of the abuse-related effects of cocaine, and (4) in vivo analysis of the PAT-cocaine neurochemical interactions. This research is undertaken by a multidisciplinary team of researchers for preclinical development of novel compounds that likely will translate to an innovative pharmacological intervention for cocaine abuse.