Cannabinergic Medications for Methamphetamine Addiction

治疗甲基苯丙胺成瘾的大麻药物

• 批准号: 8473835
• 负责人: Alexandros Makriyannis
• 金额: $ 68.79万
• 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/8473835
• 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.

我们最初的拨款申请提出“合成和评估用于治疗的新型 CBI 配体” 甲基苯丙胺 (METH) 成瘾。”总体研究目标是“”识别 CBI 拮抗剂和 体内功效低的 CBI 激动剂”，包括设计和合成：1) 新型 CBI 拮抗剂 中性或反向激动剂功效，包括联芳基吡唑和联芳基咪唑类似物； 2) CBI配体 不同的激动剂功效，包括 i) 基于我们的 CBI 激动剂原型的氨基烷基吲哚 (AAI) 配体 AM5983 和 ii) 基于部分激动剂 BAY59-3074 的二芳基醚磺酸盐 (BAS) 类似物。迄今为止，我们 已经实现了我们最初提案的目标，包括合成和评估新型 CBI 配体 指定的化学类别以及最有前途的化合物的体外和体内评估。 这项工作发现了一个新的 CBI 中性拮抗剂家族以及具有以下作用的 CBI 激动剂： 不同的功效。在寻找“可成药”CBI 部分激动剂的过程中，我们还将范围扩大到 包括两类新型大麻能配体，为我们提供了有希望的初步结果。 今后五年，我们要进一步推进当前工作，推动先进水平的提高。 兴奋剂成瘾候选药物进入临床前 IND 阶段。重要的是要注意 我们成功的 IND 前候选化合物和备用化合物也将有资格进行潜在有用的测试 治疗尼古丁和甲基苯丙胺成瘾的药物。为了实现我们的目标，我们将设计， 合成并表征新一代中性 CBI 拮抗剂，其整体药理学得到改善 配置文件作为我们当前 CBI 中性拮抗剂类别的潜在后备。主要努力是 优化将是为了获得有效且安全的 IND 候选药物。这将涵盖两者 吡唑和咪唑类似物具有良好的脑渗透性和增强的口服生物利用度。 我们还将开发低激动剂功效的新型 CBI 选择性激动剂。我们将持续优化 目前研究的两类 CBI 激动剂（AAI、BAS）具有 CB1/CB2 选择性、低 CBI 功效和 成药性概况，并扩展可用的 SAR 以从两个中识别可成药候选药物 其他大麻能类别（金刚烷基大麻素和（+）-大麻二酚类似物，具有绝对 与天然存在的 (-)-大麻二酚相反的立体化学。最有前途的化合物来自 这些合成程序将被进一步研究，以确定它们的 a) 体外活性和 b) 相对能力 穿过血脑屏障。根据这些数据，将选择新的配体进行体内研究 确定 a) 使用 CBI 介导的低温和操作测定的行为特征，尤其是 旨在识别大鼠和猴子中的低效激动剂，对于最有利的候选者， b) 使用药物歧视和静脉注射来减弱甲基苯丙胺与复发相关的影响。自我管理 猴子的程序。