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

摘要 吗啡、可待因和芬太尼等阿片类药物为数百万人提供了挽救生命的镇痛作用， 否则不可能进行医疗干预。这些益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-和阿片类药物使用障碍（OUD）。OUD反映了一个周期， 增加使用、依赖和戒断，最终引发呼吸危机。cdc估计 去年有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。 这些死亡中有许多是由于芬太尼和卡芬太尼等强效阿片类药物过量（OD）引起的。而 纳洛酮可以恢复呼吸，其半衰期短，需要多次给药才能逆转OD， 在初始逆转后导致复发，因为纳洛酮被消除，而非法药物持续存在。此外， 突然戒断会促使人们迅速且极其危险地重新吸毒。超出外径 在逆转中，OUD的标准治疗是用激动剂丁丙诺啡和美沙酮维持治疗。 两者都能降低复发率和死亡率，但获得和采用受到剂型、代谢缺陷、 以及滥用和转移的可能性更好的药物过量逆转和维持OUD是 迫切需要。 在这里，我们开发了化学上新颖的、有效的μ阿片受体（莫尔）拮抗剂， 部分激动剂我们目前的铅计数可以在临床前模型中超过阿片类药物过量， 半衰期，纳洛酮的关键负担。强效、低效的部分激动剂增加了较低的阿片样物质浓度， 纯粹的对抗者的令人厌恶的效果。这些药物和中效部分激动剂是维持治疗的主要药物 治疗OUD。

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.