Slow-onset long-acting dopamine transport inhibitors

在2004年10月1日至2005年9月30日期间，本研究项目取得了一定进展。我们之前已经证明，大脑中慢效多巴胺转运蛋白（DAT）的长效抑制剂增强脑电刺激奖励，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明显的慢效长效作用。这些先前的发现是用我们的慢效长效DAT抑制剂CTDP-30640的先导概念验证化合物进行的。在本报告年度，我们扩展了我们在这一领域的研究，包括我们使用计算机辅助分子药物设计和我们自己开发的多巴胺转运体的药效团模型重新设计和合成的另外两种化合物- CTDP-31345和CTDP-32476。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-32476在广泛的临床前动物试验范式中表现出与CTDP-30640和CTDP-31345基本相同的特征。此外，我们发现（与我们的先导化合物CTDP-30640一样）两种新的慢效长效DAT抑制剂的作用与可卡因的作用是可加性的，这表明它们具有共同的作用机制。综上所述，这些数据表明，新的长效慢效DAT抑制剂CTDP-31345和CTDP-32476在多种与药物成瘾相关的动物模型中都模拟了可卡因的作用，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。

During the period 01 Oct 04 to 30 Sept 05, 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 two 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 and CTDP-32476. 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.