Novel anti-cocaine D1 partial agonists

新型抗可卡因 D1 部分激动剂

基本信息

批准号：
10388367
负责人：
Wayne Wesley Harding
金额：
$ 39万
依托单位：
HUNTER COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-05-01 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10388367
关键词：
Abstinence Adenylate Cyclase Affinity Agonist Alkaloids Animals Behavior Therapy Behavior assessment Behavioral Behavioral Assay Behavioral Paradigm Binding Binding Proteins Biological Assay Biological Availability Blood - brain barrier anatomy C10 Catechols Chemicals Clinic Clinical Clinical Trials Cocaine Cocaine Abuse Cocaine Dependence Data Development Dopamine Dopamine D1 Receptor Dopamine Receptor Drug Kinetics Exhibits FDA approved Future Goals Health Human In Vitro Investigational Therapies Lead Libraries Ligands Literature Metabolic Modification Motor Oral Performance Persons Pharmaceutical Preparations Pharmacology Phenols Plasma Proteins Play Positioning Attribute Productivity Property Publications Rattus Rehabilitation therapy Relapse Research Role Route Scourge Self Administration Solubility Structure Testing Therapeutic Time Work addiction analog antagonist base behavioral study beta-arrestin blood-brain barrier penetration clinical development clinical translation cocaine self-administration cocaine use craving cytotoxicity functional group in vitro testing in vivo interest novel preclinical study prevent receptor scaffold side effect statistics stepholidine tool

项目摘要

ABSTRACT Close to a million people are addicted to or have abused cocaine according to current statistics. Moreover, there is an extremely high rate of relapse to cocaine use even after several months of abstinence. No medications are clinically available to treat cocaine addiction. Preclinical studies including our preliminary data, indicate that dopamine receptor targeting strategies that feature D1 partial agonism are promising for anti-cocaine medications development. In that regard, compounds that exhibit selective D1 partial agonism have demonstrated efficacy in cocaine self-administration and reinstatement behavioral paradigms in animals. However, the available selective D1 partial agonists suffer from poor pharmacokinetic properties (including oral bioavailability and blood-brain barrier penetrability) which precludes their clinical translation. The tetrahydroprotoberberine (THPB) chemotype is a novel scaffold from which to mine selective D1 partial agonists. In this proposal, we will solve the critical need for clinically useful D1 partial agonists by deploying strategic chemical modifications on the THPB lead compounds identified from our preliminary studies via parallel optimization of pharmacokinetic properties and D1 partial agonist pharmacologies. The long term goal of this proposal is to use the THPB framework to develop novel, bioavailable, selective D1 partial agonists for the treatment of cocaine addiction. We will test the central hypothesis that "The THPB framework may be structurally manipulated to afford novel, bioavailable and selective D1 partial agonists with the ability to reduce cocaine craving in rats ". Testing this hypothesis will engage three specific aims entailing synthesis, in vitro testing and in vivo behavioral assays. In the first specific aim, we will synthesize libraries of THPB analogues that contain bioisosteric replacements for metabolically labile functional groups in the lead THPBs, HUN4404 and HUN361. Specific Aim 2 will involve assessment of in vitro ADME properties as well as affinities and functional activities of the ligands at dopamine receptors via a variety of well-established assays for such. In Aim 3, compounds from Aim 2 that meet defined criteria for dopamine receptor activity and in vitro ADME properties will be submitted to an in vivo PK screen. Subsequently, selected compounds will be evaluated in a battery of behavioral assays relevant to cocaine addiction viz. self-administration and cocaine reinstatement. We expect to uncover novel D1 partial agonists that will be transformative in the field as novel in vivo tools and experimental anti-cocaine therapeutics.

抽象的根据当前的统计数据，将近一百万人沉迷或滥用可卡因。而且，即使节制几个月后，对于可卡因的复发率也极高。不药物在临床上可用于治疗可卡因成瘾。临床前研究包括我们的初步数据，表明多巴胺受体的靶向策略特征D1局部激动剂有望用于抗可卡因药物的开发。在这方面，表现出选择性D1局部激动的化合物已证明可卡因自我给药有效性和恢复动物的行为范例。但是，可用的选择性D1局部激动剂受苦来自不良的药代动力学特性（包括口服生物利用度和血脑屏障的渗透性）排除了他们的临床翻译。四氢前培比林（THPB）化学型是一种新颖的支架。可以挖掘选择性D1部分激动剂。在此提案中，我们将解决临床上有用的关键需求 D1部分激动剂通过在THPB铅化合物中部署战略化学修饰，从我们通过平行优化药代动力学特性和D1部分激动剂的初步研究药理学。该提案的长期目标是使用THPB框架开发新颖，生物利用，选择性D1 局部激动剂治疗可卡因成瘾。我们将测试“ THPB”的中心假设在结构上可以操纵框架，以负担得起新颖，生物利用和选择性的D1部分激动剂减少大鼠可卡因渴望的能力”。检验该假设将涉及三个具体目标合成，体外测试和体内行为测定。在第一个特定目的中，我们将合成含有代谢不稳定官能团的生物酶替代品的THPB类似物 THPB，HUN4404和HUN361。特定的目标2将涉及评估体外ADME特性以及配体在多巴胺受体上的亲和力和功能活动通过各种公认为此。在AIM 3中，符合多巴胺受体活性和体外标准的AIM 2的化合物 ADME属性将提交给体内PK屏幕。随后，选定的化合物将是在与可卡因成瘾有关的一系列行为测定中进行了评估。自我管理和可卡因复职。我们期望揭开新颖的D1局部激动剂，这些激动剂将在该领域具有变革性作为新颖体内工具和实验性抗可卡因治疗剂。