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

描述(申请人提供)：目前还没有针对可卡因滥用的药物疗法。本申请直接响应RFA-DA-07-006，解决了这一公共卫生危机。这一应用是为了开发具有5HT2a/5HT2b受体拮抗剂活性的新型5-羟色胺5HT2C受体激动剂，以减轻可卡因使用和依赖的行为和神经化学影响。临床前数据表明，脑内5HT2C受体的激活减弱了可卡因的增强作用，而可卡因的辨别性刺激和恢复作用对5HT2C激活和5HT2A阻断的衰减都很敏感。同时，脑内5HT2a受体的激活会产生拟精神病效应，而外周5HT2b受体的激活会产生心脏瓣膜病和肺动脉高压。目前，还没有报道5HT2C受体激动剂也不能激活5HT2a和/或5HT2b受体。然而，这里报道的初步数据表明，我们实验室合成的分子(1R，3S)-(-)-trans-1-phenyl-3-dimethylamino-1，2，3，4-tetrahydronaphthalene(PAT)是人5HT2C受体的全效激动剂，以及5HT2a和5HT2b受体的拮抗剂。这种在多个5-羟色胺受体上的双重活性(激活/阻断)是(-)-反式PAT所独有的，并被假设为提供无心脏毒性的可卡因成瘾的药物治疗。创新方法包括有针对性地合成新型PAT-型立体探针，以绘制选择性激活5HT2C受体的3D分子决定因素图，以及复杂的自我给药程序，以识别对PAT类似物调制敏感的可卡因滥用相关影响。毛细管电泳/激光诱导荧光的微透析将允许15秒的时间分辨可卡因自身给药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类似物的合成和定量构效关系模型，(2)PAT 5HT2亲和力和功能活性的体外表征，(3)体内行为药理学研究，以评估PAT对可卡因滥用相关效应的调节，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小组进行的，目的是临床前开发新的化合物，这可能会转化为对可卡因滥用的创新药理学干预。

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.