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

我们之前已经证明，我们的主要概念证明慢效长效多巴胺转运体（DAT）抑制剂- CTDP-30640 -增强脑电刺激奖励，增强大脑中与奖励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静脉注射可卡因的自我给药-所有这些都具有非常明显的慢效长效作用。在同一时期，我们扩展了我们在该领域的研究，包括我们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模型重新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，我们决定只运行这两种化合物中的一种，即CTDP-31345，通过全面的临床前动物筛选模式。我们发现CTDP-31345增强脑电刺激奖励，增强大脑中与奖励相关的伏隔核的细胞外多巴胺，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慢效长效作用。在一个不太乐观的情况下，我们发现CTDP-31345在药物识别动物行为范式中推广到可卡因，产生戏剧性的运动致敏，并在药理学上解毒并从先前静脉注射可卡因的习惯中行为消失的实验室大鼠中引发可卡因寻求行为的复发。我们进一步发现CTDP-31345本身支持静脉自我给药，尽管比可卡因低得多。我们进一步发现化合物CTDP-30640和CTDP-31345与可卡因的作用是加性的，表明它们具有共同的作用机制。这些数据表明，新的后续慢效长效DAT抑制剂CTDP-31345在多种与药物成瘾有关的动物模型中模仿可卡因的作用，但具有明显的慢效和明显的作用持续时间。与其他作为潜在抗成瘾药物疗法（如GBR-12909）开发的DAT抑制剂相比，我们的化合物显示出更慢的起效和更长的作用持续时间（例如，单次注射后96小时），从而证明了我们的药效团模型、我们的分子药物设计程序和我们的药物开发策略的有效性。然而，作为抗成瘾、抗渴望和抗复发药物的这种显著缓慢起效的长效DAT抑制剂的潜在效用仍有待确定。这些化合物产生剧烈的运动激活、剧烈的行为致敏和明显触发药物寻求行为复发的事实显然必须考虑在内。而且，关于潜在的作用机制，我们在报告期间进行了一系列广泛的研究，在与药物成瘾有关的多种动物模型的相同电池中，我们比较了海洛因和美沙酮的作用。我们发现美沙酮作为海洛因的竞争性功能拮抗剂。因此，经常将美沙酮作为阿片类药物成瘾的治疗方法和缓慢发作的长效DAT抑制剂作为精神兴奋剂成瘾的治疗方法进行类比，可能在机制上存在缺陷。要解决这个问题还需要进一步的研究。在纯分子药物设计水平上，在报告期间，我们还成功地设计和合成了新的慢效长效哌醋甲酯类似物，增加了多巴胺转运体的选择性。

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. We further found that the effects of compounds CTDP-30640 and CTDP-31345 are additive with those of cocaine, suggesting a common mechanism of action. These data show that the new follow-on slow-onset long-lasting DAT inhibitor CTDP-31345 mimics cocaine's actions in multiple animal models relating to drug addiction, but with pronounced slow onset and pronounced duration of action. 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. 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.