Cannabinergic Medications for Methamphetamine Addiction

治疗甲基苯丙胺成瘾的大麻药物

基本信息

批准号：
8081338
负责人：
Alexandros Makriyannis
金额：
$ 4.37万
依托单位：
NORTHEASTERN UNIVERSITY
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：
2007-05-01 至 2012-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8081338
关键词：
Affinity Agonist Alkanesulfonates Attenuated Behavior Behavioral Biochemical Biological Blood - brain barrier anatomy Chemicals Computer Simulation Country Cyclic AMP Development Disease Dose Drug Addiction Drug abuse Epidemic Food Goals Imidazole In Vitro Injection of therapeutic agent Laboratories Lead Ligands Literature Masks Methamphetamine Methamphetamine dependence Monkeys Mus Pharmaceutical Preparations Phase Physiological Procedures Public Health Pyrazoles Rattus Relapse Research SR 141716A Self Administration Series Side Stimulus Structure-Activity Relationship Testing addiction analog base combat design design and construction disorder later incidence prevention drug development drug discrimination drug of abuse drug reinforcement drug seeking behavior in vivo liquid chromatography mass spectrometry man meetings natural hypothermia neurochemistry non-drug novel prevent psychostimulant response

项目摘要

DESCRIPTION (provided by applicant): PAS-06-Q66 identifies a need for novel directions in the development of medications against drug addictions. To answer this need, we plan to synthesize and pharmacologically evaluate novel cannabinergic-1 (CB1) partial agonists and antagonists for the management of methamphetamine addiction. Methamphetamine addiction has become a world-wide epidemic, and is recognized as the most serious drug abuse problem in this country today. Addiction to methamphetamine, like other abused drugs, can be characterized as a recurring disease involving abuse, addiction, transition to drug-free status, and relapse. Different medications may be effective at different points in the cycle. We propose that CB1 partial agonists, through actions that overlap those of methamphetamine, may-assist in the transition to drug-free status and that CB1 antagonists, by dampening or masking the effects of stimuli that trigger drug-seeking behavior, may help prevent relapse. Our approach is based upon an emerging literature and our own laboratory observations indicating that a) CB1 agonists and methamphetamine have convergent neurochemical and behavioral actions; and b) CB1 antagonists may lessen the impact of drugs or conditions that instigate drug-seeking behavior. In our proposed research, we will use chemical templates that we and others have developed for cannabinergic ligands to design and construct novel lead compounds. Our goal is to generate analogs that vary in duration of action and pharmacological efficacy and will include both partial agonists and antagonists with neutral or inverse agonist activity. Our strategy will be to conduct side-by-side comparisons with the partial agonist A9THC and the inverse agonist SR141716A whenever possible. Novel CB1 ligands that meet efficacy criteria in biochemical studies will then be studied in rats to confirm their biological activity in hypothermia and drug discrimination studies. Next, we will use drug discrimination procedures to evaluate overlap in the 'subjective' effects of methamphetamine and novel CB1 partial agonists and, also, the ability of B1 antagonists to mute methamphetamine's stimulus effects. Finally, the most promising CB1 ligands will be further evaluated in our i.v. self-administration food/drug 'choice' procedures. We expect CB1 partial agonists to reduce methamphetamine's reinforcing strength, i.e., the proportion of behavior that it commands. We also expect CB1 antagonists to dampen the ability of low doses of noncontingently delivered methamphetamine to engender drug-seeking behavior, i.e., re-allocation of behavior toward i.v. injections and away from non-drug reinforcement. Overall, our proposed studies will permit highly significant progress toward the identification of cannabinergic candidates for drug development and, eventually, novel cannabinergic medications to combat different phases of methamphetamine addiction. This will be a significant contribution to the improvement of public health.

描述（由申请人提供）：PAS-06-Q66确定了针对药物成瘾的药物开发的新方向的需求。为了满足这一需求，我们计划合成和药理评估新颖的大麻能-1（CB1）部分激动剂和拮抗剂，以治疗甲基苯丙胺成瘾。甲基苯丙胺成瘾已成为全球流行病，并被认为是当今该国最严重的滥用药物问题。与其他滥用药物一样，对甲基苯丙胺的成瘾可以被描述为一种反复出现的疾病，涉及滥用，成瘾，无药物的过渡和复发。不同的药物在周期中的不同点可能有效。我们建议CB1部分激动剂通过与甲基苯丙胺的行为重叠的行动，在过渡到无药物状态的情况下可能辅助甲基苯丙胺，并且CB1拮抗剂，通过抑制或掩盖刺激的刺激或掩盖刺激的作用，可能有助于触发寻求药物的行为，。我们的方法是基于新兴文献和我们自己的实验室观察，表明a）CB1激动剂和甲基苯丙胺具有融合的神经化学和行为作用； b）CB1拮抗剂可能会减少促进毒品行为的药物或疾病的影响。在我们提出的研究中，我们将使用我们和其他人为大麻能配体开发的化学模板来设计和构建新型的铅化合物。我们的目标是产生在作用持续时间和药理学疗效方面变化的类似物，并将包括具有中性或反激活活性的部分激动剂和拮抗剂。我们的策略将尽可能与部分激动剂A9THC和反向激动剂SR141716A进行并排比较。然后将在大鼠中研究符合生化研究功效标准的新型CB1配体，以确认其在体温过低和药物歧视研究中的生物学活性。接下来，我们将使用药物歧视程序来评估甲基苯丙胺和新型CB1局部激动剂的“主观”作用的重叠，以及B1拮抗剂静音甲基苯丙胺刺激效应的能力。最后，最有希望的CB1配体将在我们的i.v.中进一步评估。自我管理食品/药物“选择”程序。我们预计CB1部分激动剂将降低甲基苯丙胺的增强力量，即它所命令的行为比例。我们还期望CB1拮抗剂能够抑制低剂量的非剂量递送甲基苯丙胺对寻求药物的行为的能力，即将行为重新分配给静脉注射。注射，远离非药物加固。总体而言，我们提出的研究将允许在鉴定药物开发的大麻能候选者方面取得高度的显着进展，并最终是新型的大麻能药物来对抗甲基苯丙胺成瘾的不同阶段。这将为改善公共卫生做出重大贡献。