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: 7914777
• 负责人: Raymond G. Booth
• 金额: $ 9.16万
• 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/7914777
• 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; 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; cocaine use; design; drug discrimination; gamma-Aminobutyric Acid; in vivo; innovation; multidisciplinary; neurobehavioral; neurochemistry; neuropsychiatry; novel; pharmacophore; pre-clinical; programs; receptor; research study; serotonin receptor

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.

目前没有可卡因滥用的药物疗法。这场公共卫生危机是在这个 直接响应RFA-DA-07-006的应用程序。此应用程序用于开发新的 5-羟色胺5 HT 2C受体激动剂药物，具有5 HT 2A/5 HT 2B受体拮抗剂活性，以减弱 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5 HT 2C受体减弱可卡因的强化作用，而辨别性刺激和 可卡因的恢复作用对5 HT 2C激活和5 HT 2A阻断的减弱敏感。 同时，脑5 HT 2A受体的激活产生拟精神病效应， 外周5 HT 2B受体产生心脏瓣膜病和肺动脉高压。目前还 没有报道5 HT 2C受体激动剂也不激活5 HT 2A和/或5 HT 2B受体。初步 然而，本文报道的数据表明，我们实验室合成的一种分子，（1 R，3S）-（-）-反式-1- 苯基-3-二甲氨基-1，2，3，4-四氢萘（PAT）是一种人5-HT 2C的全效激动剂 受体，加上5 HT 2A和5 HT 2B受体的拮抗剂。这种双重活性（激活/阻断）， 多种5-羟色胺受体是（-）-trans-PAT所特有的，并被假设为提供药理学作用 治疗可卡因成瘾而无心脏毒性。创新方法包括有针对性地合成 新型PAT型立体探针用于绘制选择性激活5 HT 2C受体的3D分子决定簇 和复杂的自我管理程序，以确定可卡因的滥用相关的影响， 到PAT类似物的调节。毛细管电泳/激光诱导荧光微透析技术 允许可卡因自我给药大鼠的神经化学变化的15秒时间分辨率， PAT治疗效果的神经化学机制。具体目的是：（1）PAT类似物的合成 和定量构效关系建模，（2）PAT 5 HT 2亲和力的体外表征， 功能活性，（3）体内行为药理学研究，以评估滥用的PAT调节- 可卡因的相关作用，和（4）PAT-可卡因神经化学相互作用的体内分析。这 研究由多学科研究人员团队进行，用于新型药物的临床前开发 这些化合物可能会转化为可卡因滥用的创新药物干预。