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

目前还没有针对可卡因滥用的药物疗法。这一公共卫生危机在这一点上得到了解决 直接响应RFA-DA-07-006的应用程序。这项申请是为开发小说而提出的 具有5HT2a/5HT2b受体拮抗剂活性的5-羟色胺5HT2C受体激动剂对大鼠心肌梗死的保护作用 可卡因使用和依赖对行为和神经化学的影响。临床前数据显示 脑内5HT2C受体可减弱可卡因的增强作用，而辨别性刺激和 可卡因的恢复效应对5HT2C的激活和5HT2A的阻断都很敏感。 同时，脑内5HT2a受体的激活会产生拟精神分裂效应，并激活 外周5HT2b受体可引起心脏瓣膜病和肺动脉高压。目前，有 没有报道5HT2C受体激动剂也不能激活5HT2a和/或5HT2b受体。初步 然而，这里报道的数据表明，我们实验室合成的一种分子(1R，3S)-(-)-反式-1- 帕金森(phenyl-3-dimethylamino-1，2，3，4-tetrahydronaphthalene，PAT)，是一种全效的人类5HT2C激动剂 受体，加上5HT2a和5HT2b受体的拮抗剂。这一双重活动(激活/封锁) 多个5-羟色胺受体是(-)-反式-PAT独有的，并被假设为提供药理作用 无心脏毒性的可卡因成瘾治疗。创新的方法包括有针对性的合成 新型PAT-型立体探针定位选择性激活5HT2C受体的3D分子决定簇 和复杂的自我管理程序，以确定与可卡因滥用相关的敏感影响 通过PAT模拟进行调制。毛细管电泳微渗析/激光诱导荧光 允许15秒的时间分辨可卡因自我给药大鼠的神经化学变化以识别 PAT治疗作用的神经化学机制。具体目标是：(1)PAT模拟合成 和定量构效关系模型，(2)PAT 5HT2亲和力和活性的体外表征 功能活性，(3)体内行为药理学研究，以评估PAT对滥用的调节- 可卡因的相关效应，以及(4)体内分析帕特-可卡因的神经化学相互作用。这 研究是由一个多学科的研究团队进行的，目的是开发新药的临床前 这些化合物可能会转化为治疗可卡因滥用的创新药理学干预措施。

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 activationof 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.