Cannabinergic Medications for Methamphetamine Addiction

治疗甲基苯丙胺成瘾的大麻药物

• 批准号: 7490233
• 负责人: Alexandros Makriyannis
• 金额: $ 4.4万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 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/7490233
• 关键词: Affinity; Agonist; Alkanesulfonates; Attenuated; Behavior; Behavioral; Biochemical; Biological; Blood - brain barrier anatomy; Chemicals; Computer Simulation; Condition; Country; Cyclic AMP; Development; Disease; Dose; Drug Addiction; Drug abuse; End Point; Epidemic; Food; Goals; Imidazole; In Vitro; Laboratories; Lead; Ligands; Literature; Masks; Methamphetamine; Monkeys; Mus; Pharmaceutical Preparations; Phase; Physiological; Procedures; Public Health; Pyrazoles; Rattus; Relapse; Research; SR 141716A; Self Administration; Series; Side; Stimulus; Structure-Activity Relationship; Testing; Today; addiction; analog; base; 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; natural hypothermia; neurochemistry; novel; prevent; psychostimulant; pyrazole; response

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. Metharnphetamine 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 ndicating 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 towardi.v. njections 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.

PAS-06-Q66 确定了针对药物成瘾药物开发的新方向的需求。 为了满足这一需求，我们计划合成新型 cannabinergic-1 (CB1) 并进行药理学评估 用于治疗甲基苯丙胺成瘾的部分激动剂和拮抗剂。冰毒 毒瘾已成为世界范围内的流行病，并被认为是世界上最严重的药物滥用问题 今天这个国家。与其他滥用药物一样，甲基苯丙胺成瘾可以被描述为 疾病反复发作，涉及滥用、成瘾、向无毒状态过渡和复发。不同的 药物可能在周期的不同阶段有效。我们建议 CB1 部分激动剂，通过 与甲基苯丙胺重叠的作用可能有助于向无毒品状态过渡，并且 CB1 拮抗剂通过抑制或掩盖引发药物寻求行为的刺激的影响，可能会有所帮助 防止复发。我们的方法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趋同的神经化学和行为特征 行动； b) CB1 拮抗剂可以减轻药物或引发药物寻求的状况的影响 行为。在我们提出的研究中，我们将使用我们和其他人开发的化学模板 大麻能配体设计和构建新型先导化合物。我们的目标是生成类似物 作用持续时间和药理功效各不相同，包括部分激动剂和拮抗剂 具有中性或反向激动剂活性。我们的策略是与 尽可能使用部分激动剂 A9THC 和反向激动剂 SR141716A。满足以下条件的新型 CB1 配体 然后将在大鼠中研究生化研究中的功效标准，以确认其生物活性 低温和药物歧视研究。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 部分激动剂的“主观”效应重叠，而且 B1 拮抗剂可减弱甲基苯丙胺的刺激作用。最后，最有前途的 CB1 配体将 在我们的静脉注射中进一步评估自我管理食物/药物“选择”程序。我们预计 CB1 部分 激动剂可以降低甲基苯丙胺的强化强度，即它的行为比例 命令。我们还预计 CB1 拮抗剂会抑制低剂量非偶然性药物的能力 递送甲基苯丙胺以产生寻求药物的行为，即重新分配行为。 注射并远离非药物强化。总的来说，我们提出的研究将具有非常重要的意义 在确定用于药物开发的大麻能候选药物并最终开发新药物方面取得了进展 用于对抗甲基苯丙胺成瘾不同阶段的大麻素药物。这将是一个 为改善公共卫生作出重大贡献。