SIGMA LIGANDS FOR THE TREATMENT OF COCAINE OVERDOSE

目前，没有有效的治疗可卡因过量的方法，可卡因造成的中毒和死亡比任何其他非法药物都严重。以前开发治疗可卡因过量的药物疗法的尝试都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，可以在严酷的活体条件下预防可卡因引起的行为毒性，例如存在于急诊室中。我们所有的化合物都是针对Sigma受体而设计的，Sigma受体是已知的可卡因结合部位。我们在老鼠身上的初步研究显示，我们的十几种化合物可以防止可卡因引起的惊厥和致命性，高达100%的治疗小鼠在正常情况下致命的过量服药后存活下来。我们最好的化合物在服药过量后服用甚至可以防止死亡。据我们所知，没有任何其他药物被报道能如此安全有效地对抗可卡因的毒副作用。初步研究还表明，我们的新型化合物极大地减弱了可卡因的运动刺激效应，表明它们有能力在一系列功能系统中缓解可卡因的行为。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受体是开发抗可卡因药物的可行但相对未被认识的底物。因此，本建议中的研究采用多学科方法：1)确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)确定涉及的大脑区域；4)确定Sigma受体是否影响可卡因的局部麻醉效果。总而言之，我们预计这些研究将导致开发治疗可卡因过量和成瘾的新的有效药物。

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.