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

急性过量和维持治疗中阿片类药物使用障碍的新疗法

• 批准号: 10705309
• 负责人: Donald R Gehlert
• 金额: $ 154.94万
• 依托单位: EPIODYNE, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10705309
• 关键词: Absence of pain sensation; Abstinence; Acute; Adoption; Adult; Affinity; Agonist; American; Anguish; Anhedonia; Antidotes; Biological Availability; Breathing; Buprenorphine; Cause of Death; Cessation of life; Chemicals; Clinical; Codeine; Communities; Dangerousness; Dependence; Development; Dosage Forms; Dose Limiting; Family; Fentanyl; Freedom; Goals; Half-Life; Human; Illicit Drugs; Intervention; Lead; Life; Ligands; Maintenance; Maintenance Therapy; Medical; Medicine; Metabolic; Methadone; Morphinans; Morphine; Naloxone; Opiate Addiction; Opioid; Opioid Antagonist; Oral; Overdose; Overdose reversal; Patients; Penetration; Pharmaceutical Preparations; Phase; Pre-Clinical Model; Productivity; Property; Rattus; Relapse; Rewards; Series; Structure; Techniques; Ventilatory Depression; Withdrawal; abuse liability; antagonist; carfentanil; improved; in vivo; mortality; mu opioid receptors; novel; novel therapeutics; opioid mortality; opioid overdose; opioid use disorder; programs; respiratory; safety study; scaffold; standard of care; therapeutic opioid

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.

抽象的 吗啡、可待因和芬太尼等阿片类药物可为数百万人提供挽救生命的镇痛作用，使 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反映了一个循环 增加使用、依赖和戒断，最终引发呼吸道危机。疾病预防控制中心估计 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。 其中许多死亡是由于芬太尼和卡芬太尼等强效阿片类药物过量 (OD) 造成的。尽管 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，并且可能 最初逆转后会导致复发，因为纳洛酮被消除，而非法药物仍然存在。进一步说，苦恼 突然的戒断会促使人们迅速而极其危险地重新吸毒。超越OD 逆转，OUD 的护理标准是使用激动剂丁丙诺啡和美沙酮进行维持治疗。 两者都可以减少复发和死亡率，但获取和采用受到剂型、代谢负担、 以及滥用和转移的可能性。用于逆转药物过量和维持 OUD 的更好药物是 急需。 我们在这里开发化学上新颖、强效的 mu-阿片受体 (MOR) 拮抗剂，低效和中效 部分激动剂。我们目前的先导化合物可以在临床前模型中击败阿片类药物过量，且具有更长的寿命 半衰期，纳洛酮的一个关键责任。强效、低效的部分激动剂会增加低阿片类药物的浓度，从而减少 纯粹拮抗剂的厌恶效应。这些，以及中等功效的部分激动剂，都导致维持治疗 OUD 的治疗方法。