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

具有 5HT2A 拮抗活性的新型 5HT2C 激动剂药物可治疗可卡因成瘾

• 批准号: 7499072
• 负责人: Raymond G. Booth
• 金额: $ 35.48万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7499072
• 关键词: Active Sites; Acute; Address; Affinity; Agonist; Amino Acids; Amphetamines; Attenuated; Behavior; Behavioral; Binding; Brain; Capillary Electrophoresis; Cardiac; Cardiotoxicity; Cardiovascular system; Catheters; Cells; Chemicals; Chinese Hamster Ovary Cell; Chronic; Cocaine; Cocaine Abuse; Cocaine Dependence; Condition; Consumption; Data; Data Reporting; Dependence; Detection; Development; Disease; Dopamine; Drug Design; Drug Evaluation; Electronics; Fluorescence; G Protein-Coupled Receptor Genes; Globus Pallidus; Glutamates; Glycine; Heart Valve Diseases; Human; In Vitro; Inositol Phosphates; Intervention; LIF gene; Lasers; Locomotion; Maps; Measures; Mediating; Membrane; Microdialysis; Modeling; Molecular; Molecular Conformation; Molecular Structure; Monitor; Motivation; Mus; Neurotransmitters; Nucleus Accumbens; Outcome; Peripheral; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Pharmacotherapy; Phospholipase C; Positioning Attribute; Preclinical Testing; Procedures; Protocols documentation; Public Health; Pulmonary Hypertension; Quantitative Structure-Activity Relationship; Rattus; Recombinants; Relapse; Reporting; Research; Research Personnel; Resolution; Risk; Rodent; Self Administration; Self-Administered; Serine; Serotonin; Stimulus; Structure; Study models; Substance Addiction; Taurine; Testing; Tetrahydronaphthalenes; Therapeutic Effect; Training; Translating; analog; attenuation; base; behavioral pharmacology; design; drug discrimination; gamma-Aminobutyric Acid; in vivo; innovation; leukemia inhibitory factor; multidisciplinary; neurobehavioral; neurochemistry; neuropsychiatry; novel; pharmacophore; pre-clinical; programs; receptor; research study; serotonin receptor

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.

描述（由申请人提供）：目前没有药物治疗可卡因滥用。本申请直接响应RFA-DA-07-006，解决了这一公共卫生危机。该申请旨在开发具有5HT2A/5HT2B受体拮抗剂活性的新型5 -羟色胺5HT2C受体激动剂药物，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，大脑5HT2C受体的激活会减弱可卡因的强化作用，而可卡因的鉴别刺激和恢复作用对5HT2C激活和5HT2A阻断的减弱都很敏感。同时，大脑5HT2A受体的激活产生拟精神作用，外周5HT2B受体的激活产生心脏瓣膜病和肺动脉高压。目前，还没有5HT2C受体激动剂不激活5HT2A和/或5HT2B受体的报道。然而，本文报道的初步数据表明，我们实验室合成的一种分子(1R,3S)-(-)-反式-1-苯基-3-二甲氨基-1,2,3,4-四氢萘（PAT）是一种对人类5HT2C受体有效的激动剂，同时也是5HT2A和5HT2B受体的拮抗剂。这种多重5 -羟色胺受体的双重活性（激活/阻断）是(-)-反式-羟色胺受体所特有的，并被假设为可卡因成瘾提供无心脏毒性的药理学治疗。创新方法包括靶向合成新型PAT型立体探针，以绘制5HT2C受体选择性激活的3D分子决定因素，以及复杂的自我给药程序，以识别对PAT类似物调节敏感的可卡因滥用相关效应。毛细管电泳/激光诱导荧光微透析将允许15秒时间分辨率的可卡因自我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。具体目的是：(1)PAT模拟物合成和定量构效关系建模；(2)体外表征PAT 5HT2亲和力和功能活性；(3)体内行为药理学研究评估PAT调节可卡因滥用相关效应；(4)体内分析PAT-可卡因神经化学相互作用。这项研究是由一个多学科研究小组进行的，旨在临床前开发新的化合物，这些化合物可能会转化为对可卡因滥用的创新药理干预。