Development of Cannabinoid Receptor Based Medications for Drug Addiction

基于大麻素受体的药物成瘾药物的开发

基本信息

批准号：
7496984
负责人：
Mark L. Trudell
金额：
$ 34.18万
依托单位：
UNIVERSITY OF NEW ORLEANS
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：
2007-09-15 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7496984
关键词：
Abstinence Affinity Agonist Attention Azetidines Behavioral Binding Biological Biological Assay Blood - brain barrier anatomy Brain Cannabinoids Cocaine Cocaine Dependence Computing Methodologies Development Dopamine Uptake Inhibitors Drug Addiction Drug user Exhibits Goals Illicit Drugs In Vitro Lead Ligands Literature Marijuana Mediating Methamphetamine National Institute of Drug Abuse Neuraxis Neurologic Permeability Pharmaceutical Preparations Pharmacotherapy Psychostimulant dependence Rattus Research Research Personnel Series Social Welfare Societies Structure System Therapeutic Therapeutic Agents Therapeutic Effect Therapeutic Studies Triazoles United States addiction attenuation azetidine base cannabinoid receptor design dopamine system drug of abuse in vivo lipophilicity liquid chromatography mass spectrometry monoamine novel pre-clinical programs psychostimulant receptor response scaffold stimulant abuse success transmission process

项目摘要

DESCRIPTION (provided by applicant): The development of new medications for the treatment of marijuana and psychostimulant abuse is extremely important to the welfare of the United States. To date great advances have been made in understanding the biological and pharmacological mechanisms of illicit drugs. Approaches to the development of a pharmacotherapy have focused on the monoamine-regulated circuitry in the central nervous system. Exploration of dopaminergic and sertonergic transmission has revealed tremendous amounts of information important to understanding mechanisms of psychostimulant abuse. However, direct modulation of these neurological systems has been unsuccessful in producing sustainable therapeutic effects. In lieu of the lack of success with monoamine therapeutics, researchers have turned attention to alternative mechanisms to effect dopaminergic transmission associated with addiction. It has been suggested that the cannabinoid receptor system can indirectly modulate dopaminergic transmission and thus mediate the effects of psychostimulants on brain circuitry. To this end, it has been suggested that cannabinoid antagonists could have potential utility as medications for psychostimulant addiction in addition to cannabinoid abuse. This proposal will focus on the development of a clinically useful cannabinoid antagonist that could have application for the treatment of cannabinoid and/or psychostimulant addiction. To achieve the goal of the proposed study the specific aims are as follows: 1. Synthesize novel compounds and characterize binding affinity at cannabinoid receptors. Ligand design rationale will utilize developing SAR for each series, lead compounds in the literature and computational methods to optimize potency and lipophilicity. 2. Synthesized compounds that exhibit potent (Ki values < 100 nM) receptor affinity will be evaluated in vitro functional assays to identify compounds with antagonist activity. 3. Compounds identified in Specific Aims A1-A2 that exhibit the most promising pharmacological profiles (antagonists) will be evaluated in vivo for the following:

描述（由申请人提供）：开发用于治疗大麻和精神刺激滥用的新药物对美国的福利非常重要。迄今为止，在了解非法药物的生物学和药理机制方面已取得了巨大进步。药物疗法开发的方法集中在中枢神经系统中单胺调节的电路上。对多巴胺能和静脉能传播的探索揭示了大量信息对于理解精神刺激滥用机制很重要。但是，这些神经系统的直接调节在产生可持续的治疗作用方面没有成功。为了代替单胺治疗剂缺乏成功，研究人员将注意力转移到替代机制上，以实现与成瘾有关的多巴胺能传播。已经提出，大麻素受体系统可以间接调节多巴胺能传播，从而介导精神刺激剂对脑电路的影响。为此，有人建议大麻素拮抗剂除了滥用大麻素外，还可以作为精神刺激成瘾的药物具有潜在的用途。该提案将着重于开发临床上有用的大麻素拮抗剂，该拮抗剂可能会应用大麻素和/或精神刺激成瘾。为了实现所提出的研究的目标，具体目的如下：1。合成新颖的化合物并表征大麻素受体处的结合亲和力。配体设计的理由将利用为每个系列的开发SAR，文献中的铅化合物和计算方法来优化效力和亲脂性。 2。将在体外功能测定中评估表现出有效（Ki值<100 nm）受体亲和力的合成化合物，以鉴定具有拮抗剂活性的化合物。 3。在特定目标A1-A2中鉴定出的化合物，表现出最有前途的药理学特征（拮抗剂），将在体内评估以下内容：