Novel Therapeutics for Opioid Use Disorder in the Acute Overdose and Maintenance Settings

摘要 像吗啡、可待因和芬太尼这样的阿片类药物为数百万人提供了挽救生命的止痛，使 否则就不可能进行医疗干预。这些好处被剂量限制责任所抵消，包括 呼吸抑制--所有阿片类药物死亡的原因--和阿片使用障碍(OUD)。OUD反映了一个循环 越来越多的使用、依赖和停药，最终会引发呼吸危机。疾控中心估计， 去年，72,000名美国人死于阿片类药物过量，这是50岁以下成年人死亡的主要原因。 其中许多死亡是由芬太尼和卡芬太尼等强力阿片类药物过量(OD)引起的。而当 纳洛酮可以恢复呼吸，其短暂的半衰期需要多次给药来逆转过量服药，并可能 在最初逆转后导致复发，因为纳洛酮在非法药物持续存在的情况下被消除。更进一步说，痛苦 急促戒毒会促使人们迅速、极其危险地重返毒品市场。超越OD 相反，OUD的标准护理是使用激动剂丁丙诺啡和美沙酮进行维持治疗。 两者都可以降低复发和死亡率，但获得和采用都受到剂型、代谢负债、 以及滥用和转移注意力的可能性。更好的药物是逆转过量和维持OUD 急需之物。 在这里，我们开发了化学上新颖、有效的莫阿片受体(MOR)拮抗剂，中低效。 部分激动剂。我们目前的领先药物可以在临床前模型中与阿片类药物过量竞争，具有更长的 半衰期，这是纳洛酮的一个关键缺陷。有效的，低效的部分激动剂增加了低阿片类药物的音调，减弱 纯粹的拮抗剂的反感效果。这些药物，以及中效的部分激动剂，是导致维持的原因。 OUD的治疗学。

Abstract Opioid drugs like morphine, codeine, and fentanyl confer life-saving analgesia for millions, enabling otherwise impossible medical interventions. These benefits are offset by dose limiting liabilities, including respiratory depression - the cause of all opioid deaths - and opioid use disorder (OUD). OUD reflects a cycle of increasing use, dependence, and withdrawal that eventually triggers a respiratory crisis. The CDC estimates that 72,000 Americans died in opioid overdose last year, the leading cause of death in adults under 50. Many of these deaths arise from overdoses (OD) of potent opioids like fentanyl and carfentanyl. While naloxone can restore breathing, its short half-life requires multiple administrations to reverse OD, and may result in relapse after initial reversal, as naloxone is eliminated while the illicit drug persists. Further, the anguish of precipitated withdrawal prompts rapid, and exceedingly dangerous, return to drug-seeking. Beyond OD reversal, the standard of care in OUD is maintenance treatment with agonists buprenorphine and methadone. Both reduce relapses and mortality, but access and adoption are limited by dosage forms, metabolic liabilities, and potential for abuse and diversion. Better medicines for overdose reversal and for OUD maintenance are urgently needed. Here we develop chemically novel, potent mu-opioid receptor (MOR) antagonists, low- and mid-efficacy partial agonists. Our current lead counds can outcompete opioid overdoses in preclinical models with a longer half-life, a key naloxone liability. The potent, low-efficacy partial agonists add a low opioid tone, diminishing the aversive effects of pure antagonists. These, and the mid-efficacy partial agonists, are leads to maintenance therapeutics for OUD.