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

项目总结/摘要 目前流行的鸦片成瘾导致美国每年近5万人死亡。 就像早期的可卡因/快克流行病一样，它对个人、家庭和社区都是毁灭性的。 和社区。长期阿片类药物使用障碍（OUD）最成功的治疗方法仍然是 一个是用美沙酮维持的这远远不能治愈，让人们功能，但仍然 对麻醉剂上瘾。虽然使用强大的阿片阻断药物，如纳洛酮和 纳洛酮，已证明在抢救阿片类药物过量的受害者的巨大价值，他们有 在长期治疗OUD中证明是令人失望的。使用这些药物往往会产生 毁灭性的戒断症状迫使病人转向鸦片类药物来缓解。更好的方法 长期的OUD治疗显然是必要的。 治疗OUD的困难源于阿片类药物的使用破坏了天然的 大脑中的动机和奖励机制。治疗成瘾需要恢复这种 机制不幸的是，阿片类药物和用于治疗OUD的药物， 阿片受体蛋白是奖赏机制的关键成分。我们需要的是一种药物 这就像一个开关，阻止鸦片的影响，同时允许奖励机制， 继续正常工作。这就需要一种新型的药物来控制蛋白质 （变构）位点。该方案采用高性能计算机建模技术，沿着 用生物学方法来寻找这种药物。如果成功的话，它将识别出 导致治疗和可能治愈阿片类药物成瘾的药物。

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.