Cannabinergic Medications for Methamphetamine Addiction

治疗甲基苯丙胺成瘾的大麻药物

• 批准号: 8429952
• 负责人: Alexandros Makriyannis
• 金额: $ 69.94万
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8429952
• 关键词: Affinity; Agonist; Alkanesulfonates; Applications Grants; Attenuated; Back; Behavior; Behavioral; Binding; Biological Assay; Biological Availability; Blood - brain barrier anatomy; Brain; Cannabidiol; Cannabinoids; Cells; Characteristics; Chemicals; Collaborations; Computer Simulation; Cyclic AMP; Data; Dose; Evaluation; Family; Florida; Food; Funding; Generations; Goals; Hemorrhage; Human; Imidazole; Imidazole-Pyrazole; In Vitro; Injection of therapeutic agent; Laboratories; Lead; Legal patent; Ligands; Literature; Measures; Mediating; Metabolic; Methamphetamine; Methamphetamine dependence; Michigan; Modeling; Monkeys; Nicotine; Nicotine Dependence; Oral; Penetration; Performance; Pharmaceutical Preparations; Preparation; Principal Investigator; Procedures; Progress Reports; Psychostimulant dependence; Public Health; Publishing; Rattus; Recovery; Relapse; Relative (related person); Research; Selection Criteria; Self Administration; Self-Administered; Series; Sodium Chloride; Specific qualifier value; Staging; Stimulus; Structure-Activity Relationship; Testing; Thiophenes; Time; Tissues; Training; Universities; Water; Work; addiction; analog; arrestin3; attenuation; base; design; drug discrimination; drug seeking behavior; electric impedance; improved; in vitro activity; in vivo; liquid chromatography mass spectrometry; natural hypothermia; nonhuman primate; novel; pharmacophore; pre-clinical; programs; prototype; research study; stereochemistry

Our initial grant application proposed "to synthesize and evaluate novel CBI ligands for the treatment of addiction to methamphetamine (METH)." The overall research goal was to ""identify CBI antagonists and CBI agonists with low in vivo efficacy" and included design and synthesis of: 1) novel CBI antagonists with neutral or inverse agonist efficacy including biarylpyrazole and biarylimidazole analogs; and 2) CBI ligands varying in agonist efficacy including i) aminoalkylindole (AAI) ligands based on our CBI agonist prototype AM5983 and ii) biarylether sulfonate (BAS) analogs based on the partial agonist BAY59-3074. To date, we have fulfilled the goals of our initial proposal including synthesis and evaluation of novel CBI ligands from the specified chemical classes as well as in vitro and in vivo evaluation of the most promising compounds. This work has led to the discovery of a new family of CBI neutral antagonists as well as CBI agonists with different efficacies. In the search for "druggable" CBI partial agonists we also have expanded our scope to include two novel classes of cannabinergic ligands that provided us with promising initial results. During the next five year period we intend to advance our current work so as to move our advanced candidate medications for stimulant addiction into the preclinical pre-IND stage. It is important to note that our successful pre-IND candidate and backup compounds also will be eligible for testing as potentially useful medications for nicotine, as well as methamphetamine, addiction. To accomplish our goals, we will design, synthesize, and characterize later generation neutral CBI antagonists with improved overall pharmacological profiles as potential back-ups for our current class of CBI neutral antagonists. The major effort of optimization will be towards obtaining efficacious and safe IND candidates. This will encompass both pyrazole and imidazole analogs with good brain penetration and enhanced oral bioavailability. We also will develop novel CBI selective agonists with low agonist efficacy. We will continue to optimize the two currently-studied classes of CBI agonists (AAI, BAS) for CB1/CB2 selectivity, low CBI efficacy and druggability profiles and, as well, extend the available SAR to identify druggable candidates from two additional cannabinergic classes (adamantyl cannabinoids and (+)-cannabidiol analogswith absolute stereochemistry opposite of the naturally occurring (-)-cannabidiol. The most promising compounds from these synthesis programs will be further studied to determine their a) in vitro elTicacy and b) relative ability to cross the blood brain barrier. Based on these data, novel ligands will be selected for in vivo studies to determine a) behavioral profiles of action using CBI-mediated hypothermia and operant assays especially designed to identify low-efficacy agonists in rats and monkeys and, for the most advantageous candidates, b) attenuation of methamphetamine's relapse-related effects using drug discrimination and i.v. selfadministration procedures in monkeys.

我们提出的最初赠款应用“合成和评估新型CBI配体用于治疗 对甲基苯丙胺成瘾（甲基苯丙胺）。“总体研究目标是“识别CBI拮抗剂和 CBI激动剂的体内功效低”，包括：1）新型CBI拮抗剂的设计和合成 中性或反激动剂的功效，包括双吡唑和双质假唑类似物； 2）CBI配体 基于CBI激动剂原型的激动剂疗效的变化包括i）氨基烷基吲哚（AAI）配体 AM5983和II）基于部分激动剂Bay59-3074的生育磺酸盐（BAS）类似物。迄今为止，我们 已经实现了我们最初提案的目标，包括对新型CBI配体的合成和评估 指定的化学类别以及最有希望的化合物的体外和体内评估。 这项工作导致发现了一个新的CBI中立拮抗剂以及CBI激动剂，并与 不同的效力。在寻找“可药”的CBI部分激动剂时，我们还将我们的范围扩大到 包括两种新型的大麻能配体，为我们提供了有希望的初始结果。 在接下来的五年期间，我们打算推进当前的工作，以提高我们的高级 临床前预定阶段的刺激性成瘾的候选药物。重要的是要注意 我们成功的预定候选人和备用化合物也有资格进行测试 尼古丁的药物以及甲基苯丙胺成瘾。为了实现我们的目标，我们将设计， 合成并表征后来一代中性CBI拮抗剂，具有改善的总体药理 轮廓作为我们目前的CBI中性拮抗剂的潜在备份。主要的努力 优化将是为了获得有效且安全的IND候选人。这将涵盖两者 吡唑和咪唑类似物具有良好的脑渗透和增强的口服生物利用度。 我们还将开发具有低激动剂功效的新型CBI选择性激动剂。我们将继续优化 目前研究的两种CBI激动剂（AAI，BAS），用于CB1/CB2选择性，CBI效力低和 可药用概况，还扩展了可用的SAR，以识别两个可吸毒的候选者 其他大麻能类别（金刚雄大麻素和（+） - 大麻二酚类似物绝对 立体化学与天然发生的（ - ） - 大麻二醇相反。来自 这些综合程序将得到进一步研究，以确定其a）体外弹性和b）相对能力 越过血脑屏障。基于这些数据，将选择新的配体进行体内研究 a）使用CBI介导的体温过低和操作分析确定行动的行为概况 旨在识别大鼠和猴子中的低效能激动剂，以及最有利的候选者， b）使用药物歧视和静脉注射甲基苯丙胺的复发相关作用衰减。自我管理 猴子的程序。