SIGMA LIGANDS FOR THE TREATMENT OF COCAINE OVERDOSE

目前，没有有效的治疗可卡因过量，它是负责更严重的中毒和死亡比任何其他非法药物。 以前开发药物治疗可卡因过量的尝试已经遇到了一个又一个失败的尝试。 最后，我们已经确定了一组药物，可以防止可卡因诱导的行为毒性，在严格的体内条件下，如将存在于急诊室。 我们所有的化合物都是针对sigma受体设计的，这是一个已知的可卡因结合位点。 我们对小鼠的初步研究表明，我们的十几种化合物可以预防可卡因诱导的惊厥和致死性，高达100%的治疗小鼠在通常致命的过量用药中存活。 我们最好的化合物甚至可以防止过量服用后死亡。 据我们所知，没有任何其他药物被报道对可卡因的毒性作用安全有效。初步研究还表明，我们的新化合物显着减弱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型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，本提案中的研究采用多学科方法：1）鉴定介导抗可卡因作用的σ受体亚型，2）评价抗可卡因药物对σ受体的特异性，3）鉴定涉及的大脑区域，4）确定σ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用于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.