D3 Receptor Compounds for the Treatment of Psychostimulant Abuse

用于治疗精神兴奋剂滥用的 D3 受体化合物

基本信息

批准号：
8135269
负责人：
ROBERT R LUEDTKE
金额：
$ 39.44万
依托单位：
UNIVERSITY OF NORTH TEXAS HLTH SCI CTR
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2014-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8135269
关键词：
Adenylate Cyclase Affinity Agonist Arizona Attenuated Behavior Behavioral Binding Binding Sites Biogenic Amines Biological Assay Blood - brain barrier anatomy Cannabinoids Cocaine Cocaine Abuse Development Drug Addiction Electrophysiology (science)Elements Evaluation Generations Goals Health Sciences In Vitro Individual Intervention Laboratories Ligands Methamphetamine Molecular Target Motor Activity Nucleus Accumbens Pathway interactions Pharmaceutical Preparations Piperazines Play Preclinical Testing Principal Investigator Property Protocols documentation Psychological reinforcement Rattus Reagent Regulation Research Research Project Grants Research Proposals Rewards Rodent Model Role Schedule Self Administration Signal Pathway Structure Testing Texas Therapeutic Agents Treatment Efficacy Universities Washington addiction base compound 30 design dopamine D3 receptor dopamine system in vitro Assay in vivo lipophilicity medical schools novel psychostimulant receptor response stimulant abuse

项目摘要

DESCRIPTION (provided by applicant): D3 Receptor Compounds for the Treatment of Psychostimulant Abuse. This application is submitted in response to RFA-DA-07-006 entitled Design, Synthesis, and Preclinical Testing of Potential Treatment Agents for Drug Addiction. This research proposal describes the a) synthesis, b) in vitro pharmacological characterization and c) in vivo evaluation of novel D3 dopamine receptor selective antagonists, partial agonists and agonists as potential therapeutic agents for the treatment of cocaine abuse. Our hypothesis is that stimulation of the D3 dopamine receptor in the nucleus accumbens plays a pivotal role in the reinforcing properties of psychostimulants. We further hypothesize that D3 dopamine receptor subtype selective compounds have potential as a new generation of D3 receptor-based pharmacotherapeutics for the treatment and/or management of individuals who abuse psychostimulants. Because of the high degree of homology between the binding sites of the D2 and D3 dopamine receptor subtypes, it has been difficult to develop authentic D3 receptor selective compounds. However, we have recently identified a panel of substituted phenyl-piperazine compounds that are > 30-fold selective for the D3 dopamine receptor subtype with varying degrees of intrinsic activity. Therefore, we are beginning to understand how the structure of these compounds influences binding and functional selectivity at D2 and D3 dopamine receptor subtypes . In Aim 1 we will synthesize a panel new compounds as part of our continuing goal to generate compounds which maximize D3 receptor selectivity while a) minimizing log P values (< 3.0), which are predictive of a drug's ability to cross the blood brain barrier and b) having varying ability to active several different signaling pathways (functional selectivity). In Aim 2 we propose to undertake an in vitro pharmacological assessment of the binding and intrinsic activity of D3 selective compounds. This will include compounds from previous studies and the limited number of new compounds (Aim 1) Our novel compounds will be evaluated for intrinsic activity at both D2 and D3 receptors using a) binding assays to examine selectivity for high and low affinity states, b) an adenylyl cyclase inhibition assay, c) a GIRK electrophysiology assay and d) a mitogenic assay. In Aim 3 we will evaluate the in vivo efficacy of our novel compounds for the ability to attenuate the a) psychostimulant-dependent increased locomotor activity and b) self-administration of cocaine. Both fixed ratio (FR) and a progressive ratio (PR) schedules will be used. In addition, compounds will be examined for their effects on reinstatement of extinguished cocaine-seeking behavior. The overall goal of this research project is to determine a) the structural elements of our compounds that determine binding and functional selectivity and b) which functional property/properties are predictive of behavioral efficacy in the rodent model of drug addiction.

描述（由申请人提供）：D3受体化合物用于治疗精神刺激滥用。该申请是针对RFA-DA-07-006的题为“设计，合成和临床前测试药物成瘾剂”的标题。该研究建议描述了a）合成，b）体外药理表征和c）新型D3多巴胺受体选择性拮抗剂，部分激动剂和激动剂的体内评估是治疗可卡因滥用的潜在治疗剂。我们的假设是，伏隔核中D3多巴胺受体的刺激在心理刺激剂的增强特性中起关键作用。我们进一步假设D3多巴胺受体亚型选择性化合物具有新一代的基于D3受体的药物治疗药，用于治疗和/或管理滥用精神刺激剂的个体。由于D2和D3多巴胺受体亚型的结合位点之间的同源性很高，因此很难开发正宗的D3受体选择性化合物。但是，我们最近确定了一组取代的苯基吡啶嗪化合物，对于D3多巴胺受体亚型的选择性> 30倍，内在活性不同。因此，我们开始了解这些化合物的结构如何影响D2和D3多巴胺受体亚型的结合和功能选择性。在AIM 1中，我们将合成一个新化合物，作为我们持续目标的一部分，以产生最大化D3受体选择性的化合物，而a）最小化log P值（<3.0），这些（<3.0）可以预测药物越过血脑屏障和脑屏障的能力b）具有不同能力的能力（功能选择性）。在AIM 2中，我们建议对D3选择性化合物的结合和内在活性进行体外药理评估。这将包括以前研究的化合物，新的化合物数量有限（AIM 1）我们的新型化合物将使用A）使用A）结合测定法对D2和D3受体的内在活性进行评估，以检查高和低亲和力的选择性，b）腺苷酸环化酶抑制测定法，c）Girk电生理测定法和D）有丝分裂测定法。在AIM 3中，我们将评估新型化合物的体内功效，以减轻a）心理抗抑制剂依赖性的运动活性和b）可卡因的自我给药。固定比率（FR）和渐进比率（PR）计划都将使用。此外，将检查化合物对恢复可卡因寻求可卡因行为的影响。该研究项目的总体目标是确定a）确定结合和功能选择性的化合物的结构元素以及b）哪些功能性能/特性可以预测药物成瘾模型中的行为效率。