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.

抽象的根据目前的统计数据，近一百万人对可卡因上瘾或滥用。而且，即使在戒断几个月后，可卡因的复吸率也极高。不临床上可使用药物来治疗可卡因成瘾。包括我们的初步数据在内的临床前研究表明，多巴胺受体靶向策略 D1 部分激动功能有望用于抗可卡因药物的开发。在这方面，具有选择性 D1 部分激动作用的化合物已在可卡因自我给药中表现出功效和恢复动物的行为范式。然而，可用的选择性 D1 部分激动剂受到了影响药代动力学特性差（包括口服生物利用度和血脑屏障渗透性）妨碍了它们的临床转化。四氢原小檗碱 (THPB) 化学型是一种新型支架用于挖掘选择性 D1 部分激动剂。在本提案中，我们将解决临床上有用的关键需求 D1 部分激动剂，通过对 THPB 先导化合物进行战略性化学修饰，从我们通过药代动力学特性和 D1 部分激动剂的并行优化进行初步研究药理学。该提案的长期目标是利用 THPB 框架开发新颖的、生物可利用的、选择性的 D1 用于治疗可卡因成瘾的部分激动剂。我们将检验中心假设“THPB 可以在结构上操纵框架以提供新颖的、生物可利用的和选择性的 D1 部分激动剂减少老鼠对可卡因的渴望的能力“。测试这一假设将涉及三个具体目标：合成、体外测试和体内行为测定。在第一个具体目标中，我们将综合以下库 THPB 类似物含有生物等排替代物，可替代先导代谢不稳定的官能团 THPB、HUN4404 和 HUN361。具体目标 2 将涉及体外 ADME 特性的评估以及通过各种成熟的测定法确定配体对多巴胺受体的亲和力和功能活性对于这样的。在目标 3 中，来自目标 2 的化合物满足多巴胺受体活性和体外定义的标准 ADME 属性将提交至体内 PK 筛选。随后，选定的化合物将被通过一系列与可卡因成瘾相关的行为测定进行评估。自我给药和可卡因复职。我们期望发现新颖的 D1 部分激动剂，这些激动剂将在该领域带来变革体内工具和实验性抗可卡因疗法。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Synthesis, pharmacological evaluations, and molecular docking studies on a new 1,3,4,11b-tetrahydro-1H-fluoreno[9,1-cd]azepine framework: Rigidification of D1 receptor selective 1-phenylbenzazepines and discovery of a new 5-HT6 receptor scaffold.

新型1,3,4,11b-四氢-1H-芴[9,1-cd]氮杂卓框架的合成、药理学评价和分子对接研究：D1受体选择性1-苯基苯并氮杂卓的刚性化和新5-苯并氮杂卓的发现

DOI：
发表时间：
2020
期刊：
影响因子：
3
作者：
Giri, Rajan;Alberts, Ian;Harding, Wayne W
通讯作者：
Harding, Wayne W

(-)-Stepholidine blocks expression, but not development, of cocaine conditioned place preference in rats.

(-)-Stepholidine 阻断大鼠中可卡因条件性位置偏好的表达，但不阻断其发育。

DOI：
发表时间：
2020
期刊：
影响因子：
2.5
作者：
Bennett, A;Barrera, E;Namballa, H;Harding, W;Ranaldi, R
通讯作者：
Ranaldi, R

Synthesis and dopamine receptor pharmacological evaluations on ring C ortho halogenated 1-phenylbenzazepines.

C环邻位卤代1-苯基苯并氮杂卓的合成和多巴胺受体药理学评价。

DOI：
10.1016/j.bmcl.2020.127305
发表时间：
2020-08-01
期刊：
Bioorganic & medicinal chemistry letters
影响因子：
2.7
作者：
R. Giri;H. Namballa;A. Sarker;I. Alberts;W. Harding
通讯作者：
W. Harding

Fluoroalkoxylated C-3 and C-9 (S)-12-bromostepholidine analogues with D1R antagonist activity.

具有 D1R 拮抗剂活性的氟烷氧基化 C-3 和 C-9 (S)-12-bromostepholidine 类似物。

DOI：
发表时间：
2023-12
期刊：
影响因子：
5.1
作者：
Namballa, Hari K;Decker, Ann M;Dorogan, Michael;Gudipally, Ashok;Goclon, Jakub;Harding, Wayne W
通讯作者：
Harding, Wayne W

Structural manipulation of aporphines via C10 nitrogenation leads to the identification of new 5-HT7AR ligands.

通过 C10 氮化对阿朴啡进行结构操作，从而鉴定出新的 5-HT7AR 配体。