Slow-onset long-acting dopamine transport inhibitors for

在2005年10月1日至2006年9月30日期间，这一研究项目取得了一定的进展。我们之前已经证明，大脑中的多巴胺转运体(DAT)的慢效长效抑制剂可以增强电刺激大脑的奖赏，增强大脑中与奖赏相关的伏隔核中的细胞外多巴胺，刺激运动活动，并显著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显著的慢效长效作用。这些先前的发现是通过我们针对这种慢效长效DAT抑制剂WORK-CTDP-30640的铅概念验证化合物得出的。在本报告年度，我们扩大了在这一领域的研究，包括我们使用计算机辅助分子药物设计从头设计和合成的另外三种化合物，以及我们自己开发的多巴胺转运体的药效团模型-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，在这一组广泛的临床前动物试验范例中，CTDP-32476显示了与CTDP-30640和CTDP-31345基本相同的概况。此外，我们发现(与我们的先导化合物CTDP-30640一样)这两种新的缓效长效DAT抑制剂的作用与可卡因的作用相加，表明了共同的作用机制。综上所述，这些数据表明，新的后续缓效长效DAT抑制剂CTDP-31345和CTDP-32476都模拟可卡因？S在多种与药物成瘾有关的动物模型中的作用，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。显然，这些化合物能够产生剧烈的运动激活、剧烈的行为敏感化，以及明显地引发对寻求毒品行为的复发。关于潜在的作用机制，在报告所述期间，我们进行了一系列广泛的研究，在同一组与药物成瘾有关的多种动物模型中，我们比较了海洛因和美沙酮的作用。我们发现美沙酮是海洛因的竞争性功能拮抗剂，而我们的缓效长效DAT抑制剂与可卡因具有功能相加的作用。因此，经常将美沙酮作为阿片成瘾的治疗方法与缓效、长效的DAT抑制剂作为可卡因成瘾的治疗方法之间的类比可能是机械上有缺陷的。这个问题还需要进一步的研究来解决。在纯分子药物设计水平上，在报告期内，我们成功地设计和合成了新的起效慢、持续时间长的哌甲酸甲酯类似物，增加了对多巴胺转运体的选择性。

During the period 01 Oct 05 to 30 Sept 06, modest progress was made on this research project. We had previously shown that slow-onset long-acting inhibitors of the dopamine transporter (DAT) in the brain enhance electrical brain-stimulation reward, enhance extracellular dopamine in the reward-related nucleus accumbens locus in the brain, stimulate locomotor activity, and significantly reduce intravenous cocaine self-administration in laboratory rats - all with a very pronounced slow-onset long-acting profile of action. Those previous findings had been made with our lead proof-of-concept chemical compound for this slow-onset long-acting DAT inhibitor work - CTDP-30640. During the present reporting year, 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 model of the dopamine transporter 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 (as with our lead compound CTDP-30640) the effects of the two new slow-onset long-lasting DAT inhibitors are additive with those of cocaine, suggesting a common mechanism of action. Taken together, these data show that the new follow-on slow-onset long-lasting DAT inhibitors CTDP-31345 and CTDP-32476 both mimic cocaine?s actions in multiple animal models relating to drug addiction, but with pronounced slow onsets and pronounced durations 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, while our slow-onset long-lasting DAT inhibitors act in a functionally additive manner with cocaine. Thus, the analogy frquently drawn between methadone as a treatment for opiate addiction and slow-onset long-lasting DAT inhibitors as treatments for cocaine 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 successfully designed and synthesized new slow-onset long-duration methylphenidate analogs with increased selectivity for the dopamine transporter.