Novel Functionally-Selective Serotonin 5HT2 Drugs for Amphetamines Abuse/Disorder

用于治疗安非他明滥用/疾病的新型功能选择性血清素 5HT2 药物

基本信息

批准号：
8715749
负责人：
Raymond G. Booth
金额：
$ 30.98万
依托单位：
NORTHEASTERN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-30 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8715749
关键词：
Address Adrenergic Agents Adverse effects Affinity Agonist American Amines Amphetamine Abuse Amphetamine Addiction Amphetamines Antipsychotic Agents Attenuated Behavior Behavioral Behavioral Mechanisms Behavioral Model Binding Binge Eating Biological Assay Brain Cardiac Cattle Cells Cocaine Data Development Dimethylamines Disease Docking Dopamine Drug Kinetics Eating Disorders Effectiveness FDA approved Family G Protein-Coupled Receptor Genes Goals Histamine Human Human Cloning In Vitro Inhibitory Concentration 50 Intake International Legal patent Ligands Literature Locomotion Medicine Methamphetamine Methamphetamine dependence Methods Modeling Modification Molecular Molecular Models Motor Activity Neurons Obesity Outcome Peripheral Pharmaceutical Preparations Pharmacology Pharmacotherapy Phenotype Probability Procedures Proteins Psychostimulant dependence Psychotic Disorders Publishing Pulmonary Hypertension Rattus Relapse Relative (related person)Reporting Research Rhodopsin Rodent Rodent Model Schizophrenia Secure Self Administration Serotonin Structure Structure-Activity Relationship System Therapeutic Therapeutic Agents Therapeutic Uses Translating United States National Institutes of Health Weight Gain addiction adrenergic analog attenuation base design dimethylamine drug addiction pharmacotherapy drug development drug discrimination enantiomer improved in vivo innovation interest methamphetamine abuse molecular modeling neuropsychiatry novel preclinical study psychostimulant receptor scaffold single molecule stimulant abuse success

项目摘要

ABSTRACT: This research is to advance novel internationally-patented phenylaminotetralin (PAT) analogs as functionally-selective serotonin 5HT2 receptor-based drug development candidates to treat amphetamine and methamphetamine addiction and drug-induced psychotic disorders. Activation of brain 5HT2C receptors or antagonism/inverse agonism of 5HT2A receptors attenuates psychostimulant effects in rodents. With the exception of PATs, all compounds reported in the literature that activate 5HT2C receptors also activate 5HT2A and/or 5HT2B receptors-unfortunately, activation of brain 5HT2A receptors produces psychotomimetic effects and activation of peripheral 5HT2B receptors produces cardiac valvulopathy and pulmonary hypertension. Conversely, co-antagonism of 5HTC and 5HT2A receptors contributes to weight-gain associated with antipsychotic drugs. PATs uniquely demonstrate 5HT2C receptor agonism simultaneously with 5HT2A and 5HT2B inverse agonism-this 5HT2 functional selectivity translates in vivo to therapeutic activity in behavioral models of amphetamine/methamphetamine addiction and induced psychoses, with no overt adverse effects (including, weight-gain) after peripheral administration in rodents. This novel 5HT2 functionally-selective single molecule approach is an advance over approaches targeting dopamine neuronal proteins that have proven to be sub-optimal for drug addiction pharmacotherapy, while multiple or bi-valent serotonin 5HT2 compounds pose numerous ADMET limitations. Based on a preliminary in vivo structure-activity relationship, we will optimize the PAT molecular scaffold for activity to attenuate amphetamine/methamphetamine addiction by synthesis of at least 50 novel single-enantiomer PATs with modifications to the (C2) amine, (C4) pendant phenyl, and tetrahydronaphthyl moieties. In vitro pharmacology studies include determination of PAT 5HT2A, 2B, and 2C affinity (Ki) and function (EC50/IC50). PAT docking studies using 5HT2 receptor molecular models will characterize PAT-5HT2 molecular interactions for design of additional target molecules. Modeling of 5HT2 GPCRs is based on homology to the structure of the human adrenergic ¿2 GPCR, an innovative advance over previous models that used homology to the bovine rhodopsin GPCR. Potent and efficacious PAT 5HT2C agonists with 5HT2A/2B inverse agonism are promoted to preclinical studies to evaluate pharmacotherapeutic efficacy in vivo to attenuate amphetamine and methamphetamine addiction and drug-induced psychotic disorders. A systematic behavioral analysis of PATs is undertaken to provide information on pharmacokinetic variables, functional activity in the 5HT2 system regarding 5HT2A inverse agonism vs. 5HT2C agonism, and attenuation of drug-induced psychotic disorders. Studies include using amphetamine and methamphetamine drug discrimination and self-administration procedures to validate 5HT2 receptor systems as targets for stimulant pharmacotherapies and assess attenuation of the reinforcing effects of these stimulants in a variety of behavioral procedures designed to mimic critical aspects of an addiction-like behavioral phenotype.

摘要：本研究旨在推进新型国际专利苯氨基四氢萘 (PAT) 类似物基于功能选择性血清素 5HT2 受体的候选药物开发，用于治疗安非他明和甲基苯丙胺成瘾和药物引起的精神障碍或大脑 5HT2C 受体的激活。 5HT2A 受体的拮抗/反向激动作用减弱了啮齿类动物的精神兴奋作用。除 PAT 外，文献中报道的所有激活 5HT2C 受体的化合物也会激活 5HT2A 和/或 5HT2B 受体——不幸的是，大脑 5HT2A 受体的激活会产生拟精神病作用外周 5HT2B 受体的激活会导致心脏瓣膜病和肺动脉高压。离线时，5HTC 和 5HT2A 受体的共同拮抗作用有助于体重增加 PAT 独特地表现出与 5HT2A 的 5HT2C 受体激动作用，同时具有抗精神病药物的作用。 5HT2B 反向激动——这种 5HT2 功能选择性在体内转化为行为治疗活性安非他明/甲基安非他明成瘾和精神诱导模型，没有明显的副作用啮齿动物外周给药后（包括体重增加）这种新型 5HT2 功能选择性单一药物。分子方法是针对多巴胺神经元蛋白的方法的进步，多巴胺神经元蛋白已被证明可以对于药物成瘾药物治疗来说不是最佳选择，而多种或二价血清素 5HT2 化合物基于初步的体内结构-活性关系，我们将提出许多 ADMET 局限性。优化 PAT 分子支架的活性，通过以下方式减轻苯丙胺/甲基苯丙胺成瘾：合成至少 50 种新型单对映体 PAT，并对 (C2) 胺、(C4) 侧链进行修饰苯基和四氢萘基部分的体外药理学研究包括 PAT 5HT2A 的测定。使用 5HT2 受体分子模型进行 2B 和 2C 亲和力 (Ki) 和功能 (EC50/IC50) 对接研究。将表征 PAT-5HT2 分子相互作用，以设计其他目标分子的模型。 GPCR 基于与人类肾上腺素能结构的同源性 ¿ 2 GPCR，一个创新的进步先前的模型使用与牛视紫红质 GPCR 的同源性，有效且有效的 PAT 5HT2C。具有5HT2A/2B反向激动作用的激动剂被提升到临床前研究以评估药物治疗体内减轻苯丙胺和甲基苯丙胺成瘾和药物引起的精神病的功效对 PAT 进行系统的行为分析以提供药代动力学信息。变量、5HT2系统中关于5HT2A反向激动与5HT2C激动的功能活动，以及研究包括使用安非他明和甲基苯丙胺减轻药物引起的精神障碍。药物歧视和自我给药程序，以验证 5HT2 受体系统作为目标兴奋剂药物疗法并评估这些兴奋剂在各种情况下的增强作用的衰减旨在模仿成瘾样行为表型的关键方面的行为程序。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A new class of 5-HT2A /5-HT2C receptor inverse agonists: Synthesis, molecular modeling, in vitro and in vivo pharmacology of novel 2-aminotetralins.

一类新的 5-HT2A /5-HT2C 受体反向激动剂：新型 2-氨基四氢化萘的合成、分子建模、体外和体内药理学。

DOI：
发表时间：
2022-06
期刊：
影响因子：
7.3
作者：
Casey, Austen B;Mukherjee, Munmun;McGlynn, Ryan P;Cui, Meng;Kohut, Stephen J;Booth, Raymond G
通讯作者：
Booth, Raymond G

Synthesis of novel 5-substituted-2-aminotetralin analogs: 5-HT1A and 5-HT7 G protein-coupled receptor affinity, 3D-QSAR and molecular modeling.

新型 5-取代-2-氨基四氢化萘类似物的合成：5-HT1A 和 5-HT7 G 蛋白偶联受体亲和力、3D-QSAR 和分子建模。

DOI：
发表时间：
2020
期刊：
影响因子：
3.5
作者：
Perry, Charles K;Casey, Austen B;Felsing, Daniel E;Vemula, Rajender;Zaka, Mehreen;Herrington, Noah B;Cui, Meng;Kellogg, Glen E;Canal, Clinton E;Booth, Raymond G
通讯作者：
Booth, Raymond G

Head-twitch response in rodents induced by the hallucinogen 2,5-dimethoxy-4-iodoamphetamine: a comprehensive history, a re-evaluation of mechanisms, and its utility as a model.

致幻剂 2,5-二甲氧基-4-碘苯丙胺引起的啮齿类动物的头部抽搐反应：全面的历史、机制的重新评估及其作为模型的实用性。

DOI：
发表时间：
2012-07
期刊：
影响因子：
0
作者：
Canal, Clint E;Morgan, Drake
通讯作者：
Morgan, Drake

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Raymond G. Booth其他文献

Conformational analysis, pharmacophore identification, and comparative molecular field analysis of ligands for the neuromodulatory sigma 3 receptor.

神经调节 sigma 3 受体配体的构象分析、药效团鉴定和比较分子场分析。

DOI：
10.1021/jm00050a008
发表时间：
1994-11-25
期刊：
Journal of medicinal chemistry
影响因子：
7.3
作者：
A. M. Myers;P. Charifson;C. E. Owens;N. Kula;Andrew T. McPhail;Ross J. Baldessarini;Raymond G. Booth;S. Wyrick
通讯作者：
S. Wyrick