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: 9155740
• 负责人: Eliot Gardner
• 金额: $ 9.69万
• 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/9155740
• 关键词: Animal Model; Animals; Area; Behavior; Behavioral Paradigm; Biochemical; Biological Assay; Brain; Chemical Structure; Chemicals; Cocaine; Computer Assisted; Cues; Data; Development; Dopamine; Dose; Drug Addiction; Drug Design; Drug Kinetics; Electrical Stimulation of the Brain; Exposure to; Extinction (Psychology); Goals; Habits; Heroin; High Pressure Liquid Chromatography; Hour; Hunger; Immunoblotting; Injection of therapeutic agent; Intravenous; Laboratory Animals; Laboratory Rat; Lead; Light; Measures; Methadone; Methylphenidate; Microdialysis; Modafinil; Modeling; Molecular; Molecular Models; Motor Activity; Neurotransmitters; Nucleus Accumbens; Opiates; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Polymerase Chain Reaction; Procedures; Prodrugs; Proteins; Psychological reinforcement; Psychostimulant dependence; RNA; Relapse; Reporting; Research; Reverse Transcription; Rewards; Running; Sampling; Self Administration; Stress; Techniques; Testing; Time; Western Blotting; Work; addiction; analog; clinical efficacy; craving; design; dopamine transporter; drug discrimination; extracellular; in vivo; inhibitor/antagonist; molecular modeling; monoamine; mu opioid receptors; novel; pharmacophore; pre-clinical; preference; psychostimulant; research study; screening; transport inhibitor

We had previosuly shown 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 same 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-31345 itself supports intravenous self-administration, albeit at a much lower rate than cocaine. As we had previously seen with compound CTDP-30640, the effects of compound CTDP-31345 are additive with those of cocaine. This prompted us to explore the relationship between the fast-onset short-acting opiate heroin and the slow-onset long-acting opiate methadone, the latter of which is well-known to have clinical efficacy as an anti-addiction medication for patients addicted to opiates. We reasoned that investigating the heroin-methadone relationship in our preclinical animal models might shed light on medication development stratgies for cocaine and other psychostimulants. We found that - in contrast to the relationship between cocaine and CTDP-30640 or CTDP-31345 - methadone pretreatment: 1) dose-dependently inhibited intravenous heroin self-administration with a clear behavioral extinction pattern, 2) dose-dependently inhibited heroin-enhanced brain-stimulation reward, and 3) dose-dependently inhibited heroin-enhanced nucleus accumbens levels of the reward-related and relapse-related neurotransmitter dopamine as measured by in vivo brain microdialysis. This suggests a functional antagonism by methadone of heroin's actions, which may be explained by methadone's ability to produce cellular internalization of the mu opioid receptor. These data suggest that in order to be fully successful, potential anti-cocaine medications should more fully emulate methadone's action - i.e., functionally antagonizing cocaine's actions (perhaps by inducing conformational changes in the dopamine transporter) while at the same time blocking the transporter in a cocaine-like manner (but with slow-onset long-lasting pharmacokinetics) so as to substitute for cocaine and remediate the brain chemical deficiency believed to underlie cocaine "hunger" and cocaine craving. In addition, we believe that the facts that our compounds CTDP-30640 and CTDP-31345 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) demonstrate the validity of our pharmacophore drug design model, our molecular drug design procedures, and our pro-drug medication development strategy. On a purely molecular drug design level, during the reporting period we successfully designed and synthesized new slow-onset long-duration methylphenidate analogs with increased selectivity for the dopamine transporter, resulting in a new test compound - CTDP-32476. Preliminary experiments with CTDP-32476 suggest that it may have potential utility as an effective anti-addiction pharmacotherapy for psychostimulant addiction. Further experiments with CTDP-32476 to fully characterize its anti-addiction potential are planned. In addition, during the present reporting period we began to work on modafinil as a potential anti-addicton pharmacotherapeutic compound.

我们之前已经证明，我们的铅概念验证慢效长效多巴胺转运体抑制剂-CTDP-30640-增强了电刺激大脑的奖赏，增强了大脑中与奖赏相关的伏隔核中的细胞外多巴胺，刺激了运动活动，并显著减少了实验大鼠静脉注射可卡因的自我给药-所有这些都具有非常显著的慢效长效作用。在同一时期，我们扩展了我们在这一领域的研究，包括另外三种我们使用计算机辅助分子药物设计从头合成的化合物，以及我们自己开发的药效团DAT模型-CTDP-31345、CTDP-31346和CTDP-32476。由于CTDP-31345和CTDP-31346的化学结构高度相似，决定只对这两种化合物中的一种进行全面的临床前动物筛选范例-CTDP-31345。我们发现，CTDP-31345增强了电刺激大脑的奖赏，增强了大脑中与奖赏相关的伏隔核部位的细胞外多巴胺，刺激了运动活动，并显著减少了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显著的慢效和长效作用。在一个不太有希望的方面，我们发现CTDP-31345在药物识别动物行为范式中概括为可卡因，产生戏剧性的运动敏化，并触发实验室大鼠复发到寻找可卡因的行为，这些大鼠已经被药物解毒，并从行为上消除了以前静脉注射可卡因的习惯。我们进一步发现，CTDP-31345本身支持静脉注射自我给药，尽管其速度比可卡因低得多。正如我们之前看到的化合物CTDP-30640，化合物CTDP-31345的作用与可卡因的作用是相加的。这促使我们探索快效短效阿片类海洛因与慢效长效阿片类美沙酮之间的关系，后者是众所周知的，作为阿片成瘾患者的抗成瘾药物具有临床疗效。我们认为，在我们的临床前动物模型中研究海洛因和美沙酮的关系可能会为可卡因和其他精神刺激剂的药物开发战略提供帮助。与可卡因与CTDP-30640或CTDP-31345-美沙酮处理的关系相比，我们发现：1)剂量依赖地抑制海洛因静脉给药并有明确的行为消退模式，2)剂量依赖地抑制海洛因增强的脑刺激奖赏，3)剂量依赖地抑制海洛因增强的伏隔核多巴胺水平，这与活体脑微透析测量的奖赏相关和复发相关神经递质的水平有关。这表明美沙酮对海洛因的作用具有功能性拮抗作用，这可能是由于美沙酮能够产生u阿片受体的细胞内化。这些数据表明，为了取得完全的成功，潜在的反可卡因药物应该更充分地模仿美沙酮的作用-即在功能上拮抗可卡因的作用(可能通过诱导多巴胺转运体的构象变化)，同时以类似可卡因的方式阻止转运体(但具有缓慢起效的长期药代动力学)，以替代可卡因，并补救据信是导致可卡因“饥饿”和对可卡因渴望的大脑化学物质缺乏。此外，我们相信，我们的化合物CTDP-30640和CTDP-31345与其他被开发为潜在的抗成瘾药物疗法的DAT抑制剂(例如，GBR-12909)相比，表现出更慢的起效时间和更长的作用持续时间(例如，单次注射后96小时)，这一事实证明了我们的药效团药物设计模型、我们的分子药物设计程序和我们的亲药物药物开发战略的有效性。在纯分子药物设计水平上，在本报告所述期间，我们成功地设计和合成了新的起效慢、持续时间长的哌酸甲酯类似物，增加了对多巴胺转运体的选择性，从而产生了新的测试化合物-CTDP-32476。CTDP-32476的初步实验表明，它可能作为一种有效的抗成瘾药物治疗精神刺激性成瘾的潜在用途。计划用CTDP-32476进行进一步的实验，以充分表征其抗成瘾潜力。此外，在本报告所述期间，我们开始研究莫达非尼作为一种潜在的抗阿迪顿药物治疗化合物。