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

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。我们进一步发现，虽然化合物CTDP-30640的作用与可卡因的作用是相加的，这表明了共同的作用机制，但化合物CTDP-31345的作用与可卡因的作用不是相加的，这表明苯基四胺系列化合物可能比吲哚胺系列化合物产生更多有用的化合物。这些数据表明，新的后续缓效长效DAT抑制剂CTDP-31345在与药物成瘾有关的多种动物模型中模拟可卡因的作用，但具有明显的缓慢起效和明显的作用持续时间。与其他被开发为潜在的抗成瘾药物疗法(例如，GBR-12909)的DAT抑制剂相比，我们的化合物表现出更慢的起效速度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亲药物药物开发战略的有效性。然而，诸如抗成瘾、抗渴求和抗复发药物等显著缓慢起效和长效的DAT抑制剂的潜在效用仍有待确定。因此，在本报告所述期间，我们启动了一系列全新的实验--在同一组与药物成瘾有关的多种动物模型中，对比了叠加在海洛因上的美沙酮和CTDP-31345对可卡因的影响。我们发现美沙酮是海洛因的竞争性功能拮抗剂。而且，虽然还没有完全完成，但这些实验表明，化合物CTDP-31345对可卡因行为的阻断作用比CTDP-30640更明显。事实上，CTDP-30640产生戏剧性的运动激活，戏剧性的行为敏化，并明确地触发复发到寻求药物的行为，这使得吲哚胺化学系列成为建立潜在的抗精神刺激治疗药物的不良模板。在纯分子药物设计水平上，在报告期内，我们还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，从而产生了我们的新测试化合物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。

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 while the effects of compound CTDP-30640 are additive with those of cocaine, suggesting a common mechanism of action, the effects of the compound CTDP-31345 are not additive with those of cocaine, suggesting that the phenyltetraline chemical series may yield more useful compounds than the indanamine chemical series. 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. We therefore initiated an entirely new series of experiments during this reporting period - contrasting the effects of methadone superimposed upon heroin with the effects of CTDP-31345 upon cocaine, in the same battery of multiple animal models relating to drug addiction. We found that methadone acts as a competitive functional antagonist of heroin. And, while not yet fully completed, these experiments show that compound CTDP-31345 has more pronounced blocking effects on cocaine's actions than CTDP-30640. The fact that CTDP-30640 produces dramatic locomotor activation, dramatic behavioral sensitization, and clear triggering of relapse to drug-seeking behavior makes the indanamine chemical series a poor template upon which to built potential anti-psychostimulant therapeutic agents. 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 - resulting in our 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.