Slow-onset long-acting dopamine transport inhibitors for treating drug addiction

用于治疗药物成瘾的缓效长效多巴胺转运抑制剂

• 批准号: 7593285
• 负责人: ELIOT L GARDNER
• 金额: $ 37万
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7593285
• 关键词: Accounting; Agonist; Animal Model; Animal Testing; Animals; Area; Behavior; Behavioral Paradigm; Biochemical; Biological Assay; Brain; Chemical Structure; Chemicals; Cocaine; Computer Assisted; Condition; Cues; Data; Development; Dopamine; Drug Addiction; Drug Design; Electrical Stimulation of the Brain; Exposure to; GBR-12909; Goals; Habits; Heroin; High Pressure Liquid Chromatography; Hour; Immunoblotting; Injection of therapeutic agent; Intravenous; Laboratory Animals; Laboratory Rat; Lead; Ligands; Methadone; Methylphenidate; Microdialysis; Modeling; Molecular; Molecular Models; Motor Activity; Nucleus Accumbens; Opiate Addiction; Pharmaceutical Preparations; Pharmacotherapy; Polymerase Chain Reaction; Procedures; Prodrugs; Proteins; Psychological reinforcement; Psychostimulant dependence; RNA; Range; Relapse; Reporting; Research; Research Project Grants; Reverse Transcription; Rewards; Running; Sampling; Screening procedure; Self Administration; Series; Stress; Techniques; Testing; Western Blotting; Work; addiction; analog; behavioral sensitization; concept; craving; design; dopamine D3 receptor; dopamine transporter; drug discrimination; drug seeking behavior; extracellular; in vivo; inhibitor/antagonist; monoamine; novel; pharmacophore; pre-clinical; preference; transport inhibitor

During the period 01 Oct 06 to 30 Sept 07, modest progress was made on this research project. During this period, we showed that our lead proof-of-concept slow-onset long-acting dopamine transporter (DAT) inhibitor - CTDP-30640 - enhances electrical brain-stimulation reward, enhances extracellular dopamine in the reward-related nucleus accumbens locus in the brain, stimulates locomotor activity, and significantly reduces intravenous cocaine self-administration in laboratory rats - all with a very pronounced slow-onset long-acting profile of action. During this sdame period, we extended our research in this area to include three additional compounds that we designed and synthesized de novo using computer-assisted molecular drug design and a pharmacophore DAT model that we ourselves developed - CTDP-31345, CTDP-31346, and CTDP-32476. Because of the high degree of similarity between the chemical structures of CTDP-31345 and CTDP-31346, a decision was made to run only one of those two compounds through a full range of preclinical animal screening paradigms - CTDP-31345. We found that CTDP-31345 enhances electrical brain-stimulation reward, enhances extracellular dopamine in the reward-related nucleus accumbens locus in the brain, stimulates locomotor activity, and significantly reduces intravenous cocaine self-administration in laboratory rats - all with a very pronounced slow-onset long-acting profile of action. On a less promising note, we found that CTDP-31345 generalizes to cocaine in the drug-discrimination animal behavioral paradigm, produces dramatic locomotor sensitization, and triggers relapse to cocaine-seeking behavior in laboratory rats who has been pharmacologically detoxified and behaviorally extinguished from their prior intravenous cocaine-taking habits. We further found that CTDP-32476 displays essentially the same profile as CTDP-30640 and CTDP-31345 in this extensive battery of preclinical animal test paradigms. Further, we found that the effects of our lead compound CTDP-30640 are fully additive with those of cocaine, suggesting a common mechanism of action. However, to our surprise, the effects of CTDP-31345 and cocaine, while still significantly additive, are less than fully additive. This suggests that CTDP-31345 may function to some degree as a partial agonist or even to some degree as a "competitive" agonist. Taken together, these data show that the new follow-on slow-onset long-lasting DAT inhibitors CTDP-31345 and CTDP-32476 mimic cocaine's actions in multiple animal models relating to drug addiction, but with pronounced slow onsets and pronounced durations of action. And, the trans-aminotetralin compound CTDP-31345 may be more methadone-like than the indanamine compound CTDP-30640. Our compounds show much slower onsets and much longer durations of action (e.g., 96 hours following a single injection) than other DAT inhibitors developed as potential anti-addiction pharmacotherapies (e.g., GBR-12909), thus demonstrating the validity of our pharmacophore model, our molecular drug design procedures, and our pro-drug medication development strategy. However, the potential utility of such dramatically slow-onset and long-acting DAT inhibitors as anti-addiction, anti-craving, and anti-relapse medications remains to be determined. The fact that such compounds produce dramatic locomotor activation, dramatic behavioral sensitization, and clear triggering of relapse to drug-seeking behavior must obviously be taken into account. And, with respect to underlying mechanism of action, we carried out an extensive series of studies during the reporting period in which we compared heroin's actions to methadone's actions in the same battery of multiple animal models relating to drug addiction. We found that methadone acts as a competitive functional antagonist of heroin. Thus, the analogy frquently drawn between methadone as a treatment for opiate addiction and slow-onset long-lasting DAT inhibitors as treatments for psychostimulant addiction may be mechanistically flawed, although CTDP-31345 appears more methadone-like mechanistically than does CTDP-30640. Further research is needed to resolve this issue. On a purely molecular drug design level, during the reporting period we also successfully designed and synthesized new slow-onset long-duration methylphenidate analogs with increased selectivity for the dopamine transporter.

2006年10月1日至7月30日期间，该研究项目取得了一定进展。在此期间，我们展示了我们的主要概念验证慢效长效多巴胺转运蛋白（DAT）抑制剂 - CTDP-30640 - 增强大脑电刺激奖励，增强大脑奖励相关伏核位点的细胞外多巴胺，刺激运动活动，并显着减少实验室大鼠静脉注射可卡因的自我给药 - 所有这些都具有非常明显的缓慢起效的长效作用。在此期间，我们扩展了该领域的研究，包括使用计算机辅助分子药物设计和我们自己开发的药效团 DAT 模型从头设计和合成的另外三种化合物 - CTDP-31345、CTDP-31346 和 CTDP-32476。 由于 CTDP-31345 和 CTDP-31346 的化学结构高度相似，因此决定仅通过全套临床前动物筛选范例运行这两种化合物中的一种 - CTDP-31345。我们发现 CTDP-31345 可以增强大脑电刺激奖赏，增强大脑中与奖赏相关的伏隔核位点的细胞外多巴胺，刺激运动活动，并显着减少实验室大鼠的静脉注射可卡因自我给药 - 所有这些都具有非常明显的缓慢起效的长效作用。令人不太乐观的是，我们发现 CTDP-31345 在药物歧视动物行为范式中泛化为可卡因，产生显着的运动敏化，并引发实验室大鼠的可卡因寻求行为复发，这些大鼠已通过药物解毒并在行为上消除了先前静脉注射可卡因的习惯。我们进一步发现，在广泛的临床前动物测试范例中，CTDP-32476 显示出与 CTDP-30640 和 CTDP-31345 基本相同的特征。此外，我们发现我们的先导化合物 CTDP-30640 的作用与可卡因的作用完全相加，表明有共同的作用机制。然而，令我们惊讶的是，CTDP-31345 和可卡因的效果虽然仍然显着相加，但并不完全相加。这表明 CTDP-31345 可能在某种程度上充当部分激动剂，甚至在某种程度上充当“竞争性”激动剂。总而言之，这些数据表明，新的后续缓慢起效长效 DAT 抑制剂 CTDP-31345 和 CTDP-32476 在与药物成瘾相关的多种动物模型中模仿可卡因的作用，但具有明显的缓慢起效和明显的作用持续时间。并且，反式氨基四氢化萘化合物CTDP-31345可能比茚满胺化合物CTDP-30640更像美沙酮。与其他作为潜在抗成瘾药物疗法开发的 DAT 抑制剂（例如 GBR-12909）相比，我们的化合物起效更慢，作用持续时间更长（例如单次注射后 96 小时），从而证明了我们的药效团模型、分子药物设计程序和前药药物开发策略的有效性。然而，这种起效极慢且长效的 DAT 抑制剂作为抗成瘾、抗渴求和抗复发药物的潜在用途仍有待确定。显然必须考虑到这样的化合物会产生显着的运动激活、显着的行为敏化以及明显触发寻药行为复发的事实。而且，就潜在的作用机制而言，我们在报告期内进行了一系列广泛的研究，在与毒瘾有关的同一组多个动物模型中，将海洛因的作用与美沙酮的作用进行了比较。我们发现美沙酮是海洛因的竞争性功能拮抗剂。因此，尽管 CTDP-31345 在机制上比 CTDP-30640 更类似于美沙酮，但经常将美沙酮作为阿片类药物成瘾的治疗方法与缓效长效 DAT 抑制剂作为精神兴奋剂成瘾的治疗方法进行类比，这可能在机制上存在缺陷。需要进一步研究来解决这个问题。在纯分子药物设计层面，报告期内我们还成功设计合成了新型缓释长效哌甲酯类似物，对多巴胺转运蛋白的选择性增强。