Discovering Therapeutic Agents for the Treatment of Opioid Use Disorder by Targeting Negative Allosteric Modulators of the mu-Opioid Receptor

项目摘要/摘要 目前鸦片成瘾的流行已经导致美国每年近5万人死亡。 就像早先的可卡因/可卡因流行一样，事实证明，它对个人和家庭都是毁灭性的 和社区。治疗长期阿片类药物使用障碍(OUD)最成功的方法仍然是 其中之一就是使用美沙酮进行维护。这远不是治愈的方法，让人功能正常，但仍然 对麻醉剂上瘾。而使用强力阿片类阻断药物，如纳洛酮和 纳曲酮在抢救阿片类药物过量受害者方面显示出巨大的价值，他们 事实证明，对OUD的长期治疗令人失望。这些药物的使用通常会产生 毁灭性的戒断症状迫使患者转向鸦片类药物以缓解症状。一种更好的方法 对于长期的乌德治疗显然是必要的。 治疗OUD的困难源于鸦片类药物的使用损害了自然 大脑中的激励和奖励机制。治愈成瘾需要恢复这一点 机制。不幸的是，阿片剂和用于治疗OUD的药物都损害了 阿片受体蛋白，奖励机制的关键组成部分。现在需要的是一种药物 这起到了开关的作用，阻止了鸦片类药物的影响，同时允许奖励机制 继续正常工作。这需要一种新型的药物来控制蛋白质 (变构)位点。该方案采用了高性能的计算机建模技术 用生物测试来寻找这样的药物。如果成功，它将识别出先导化合物 导致治疗并可能治愈阿片成瘾的药物。

Project Summary/Abstract The current epidemic of opiate addiction has led to nearly 50 thousand deaths a year in the U.S. Much like the earlier cocaine/crack epidemic, it has proved devastating to individuals, families and communities. The most successful treatment of long-term opiate use disorder (OUD) is still one of maintenance using methadone. This is far from a cure, leaving people functional but still addicted to a narcotic. While the use of powerful opiate blocking drugs, such as naloxone and naltrexone, has demonstrated great value in rescuing victims of opiate overdose, they have proved disappointing in the long term treatment of OUD. The use of these drugs often produces devastating withdrawal symptoms forcing patients to turn to opiates for relief. A better approach to long term OUD treatment is clearly needed. The difficulty in treating OUD stems from the fact that opiate use damages the natural motivational and reward mechanisms in the brain. Curing addiction requires restoring this mechanism. Unfortunately, both opiates and the drugs used to treat OUD, compromise the opiate receptor protein, a key component of the reward mechanism. What is needed is a drug that acts as a switch, blocking the effects of opiates while allowing the reward mechanism to continue to work normally. This requires a new type of drug that operates on the protein control (allosteric) site. The proposal employs high performance computer modeling technology along with biological assays to search for such a drug. If successful it will identify lead compounds that result in drugs that treat and possibly cure opiate addiction.