SIGMA LIGANDS FOR THE TREATMENT OF COCAINE OVERDOSE

目前，对可卡因过量没有有效的治疗方法，它造成的严重中毒和死亡比任何其他非法药物都要严重。以前开发药物疗法治疗可卡因过量的尝试一次又一次失败。最后，我们已经确定了一组药物，可以在严格的体内条件下，如急诊室中，预防可卡因引起的行为毒性。我们所有的化合物都是针对sigma受体设计的，这是一种已知的可卡因结合位点。我们在老鼠身上进行的初步研究表明，我们的十几种化合物可以预防可卡因引起的抽搐和致命，在通常致命的过量服用后，接受治疗的老鼠存活的几率高达100%。我们最好的化合物甚至可以在服用过量后防止死亡。据我们所知，还没有其他药物能像可卡因那样安全有效地对抗可卡因的毒性作用。初步研究还表明，我们的新化合物显著减弱了可卡因的运动刺激作用，表明它们有能力减轻可卡因在一系列功能系统中的作用。我们的初步研究为我们的新化合物的潜在治疗意义提供了令人信服的证据，并表明sigma受体代表了抗可卡因药物开发的可行但相对未被识别的底物。因此，本提案中的研究利用多学科方法：1)鉴定介导抗可卡因作用的sigma受体亚型，2)评估抗可卡因药物对sigma受体的特异性，3)鉴定涉及的大脑区域，以及4)确定sigma受体是否影响可卡因的局部麻醉作用。总之，我们预计这些研究将导致开发新的和有效的药物来治疗可卡因过量和成瘾。

Currently, there are no effective treatments for cocaine overdose and it is responsible for more serious intoxications and deaths than any other illicit drug. Previous attempts to develop pharmacotherapies to treat cocaine overdose have been met by one unsuccessful attempt after another. Finally, we have identified a group of drugs that can prevent cocaine-induced behavioral toxicity, under rigorous in vivo conditions, such as would exist in an emergency room. All of our compounds were designed to target sigma receptors, a known binding site for cocaine. Our preliminary studies in mice reveal that over a dozen of our compounds prevent cocaine-induced convulsions and lethality, with up to 100 percent of treated mice surviving a normally fatal overdose. Our best compound even prevents death when administered after an overdose. To our knowledge, no other drug has been reported to be as safe and effective against the toxic effects of cocaine. Initial studies also show that our novel compounds dramatically attenuate the locomotor stimulatory effects of cocaine, indicating that they have the ability to mitigate the actions of cocaine across a range of functional systems. Our preliminary studies provide compelling evidence for the potential therapeutic significance of our novel compounds, and suggest that sigma receptors represent viable, but relatively unrecognized, substrates for the development of anti-cocaine agents. Therefore, the studies in this proposal utilize a multidisciplinary approach to: 1) identify the sigma receptor subtypes that mediate the anti-cocaine actions, 2) evaluate the specificity of the anti-cocaine agents for sigma receptors, 3) identify the areas of the brain that are involved, and 4) determine whether sigma receptors influence the local anesthetic effects of cocaine. Together, we anticipate that these studies will lead to the development of new and effective agents for the treatment of cocaine overdose and addiction.