Slow-onset long-acting dopamine transport inhibitors for

点击翻译按钮获取中文摘要

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.