One of the most prominent opioid analgesics in the United States is the high potency agonist fentanyl. It is used in the treatment of acute and chronic pain and as an anesthetic adjuvant. When used inappropriately, however, ingestion of just a few milligrams of fentanyl or other synthetic opioid can cause opioid-induced respiratory depression (OIRD), often leading to death. Currently, the treatment of choice for OIRD is the opioid receptor antagonist naloxone. Recent reports, however, suggest that higher doses or repeated dosing of naloxone (due to recurrence of respiratory depression) may be required to reverse fully fentanyl-induced respiratory depression, rendering this treatment inadequate. To combat this synthetic opioid overdose crisis, this research aims at identifying a novel opioid reversal agent with enhanced efficacy towards fentanyl and other synthetic opioids. A series of naltrexone analogues were characterized for their ability to antagonize the effects of fentanyl in vitro utilizing a modified forskolin-induced cAMP accumulation assay. Lead analogue 29 was chosen to undergo further PK studies, followed by in vivo pharmacological analysis to determine its ability to antagonize opioid-induced antinociception in the hot plate assay. A series of potent MOR antagonists were identified, including the highly potent analogue 29 (IC50 = 2.06 nM). Follow-up PK studies revealed 29 to possess near 100% bioavailability following IP administration. Brain concentrations of 29 surpassed plasma concentrations, with an apparent terminal half-life of ~ 80 min in mice. In the hot plate assay, 29 dose-dependently (0.01–0.1 mg/kg; IP) and fully antagonized the antinociception induced by oxycodone (5.6 mg/kg; IP). Furthermore, the dose of 29 that is fully effective in preventing oxycodone-induced antinociception (0.1 mg/kg) was ineffective against locomotor deficits caused by the KOR agonist U50,488. Methods have been developed that have utility to identify enhanced rescue agents for the treatment of OIRD. Analogue 29, possessing potent MOR antagonist activity in vitro and in vivo, provides a promising lead in our search for an enhanced synthetic opioid rescue agent.

中文翻译：

---

一种潜在的合成阿片类药物拯救剂的设计、合成和初步评估

美国最突出的阿片类镇痛药之一是高效激动剂芬太尼。它用于治疗急性和慢性疼痛并作为麻醉辅助剂。然而，如果使用不当，仅摄入几毫克芬太尼或其他合成阿片类药物就会导致阿片类药物引起的呼吸抑制 (OIRD)，通常会导致死亡。目前，OIRD 的首选治疗方法是阿片受体拮抗剂纳洛酮。然而，最近的报告表明，可能需要更高剂量或重复给药的纳洛酮（由于呼吸抑制复发）才能完全逆转芬太尼诱导的呼吸抑制，从而导致这种治疗不足。为了应对这种合成阿片类药物过量危机，该研究旨在确定一种新型阿片类药物逆转剂，其对芬太尼和其他合成阿片类药物具有增强的功效。一系列纳曲酮类似物的特征在于它们能够利用改良的毛喉素诱导的 cAMP 积累测定在体外拮抗芬太尼的作用。选择铅类似物 29 进行进一步的 PK 研究，然后进行体内药理学分析，以确定其在热板试验中拮抗阿片类药物诱导的镇痛作用的能力。确定了一系列有效的 MOR 拮抗剂，包括高效的类似物 29 (IC50 = 2.06 nM)。后续 PK 研究显示，IP 给药后 29 种生物利用度接近 100%。29 的脑浓度超过血浆浓度，在小鼠中的明显终末半衰期约为 80 分钟。在热板试验中，29 呈剂量依赖性（0.01–0.1 mg/kg；IP）并完全拮抗羟考酮诱导的镇痛作用（5.6 mg/kg；IP）。此外，完全有效预防羟考酮诱导的镇痛作用的剂量 29 (0.1 mg/kg) 对 KOR 激动剂 U50,488 引起的运动缺陷无效。已开发出可用于鉴定用于治疗 OIRD 的增强救援剂的方法。类似物 29 在体外和体内具有有效的 MOR 拮抗剂活性，为我们寻找增强的合成阿片类药物拯救剂提供了有希望的线索。1 mg/kg) 对 KOR 激动剂 U50,488 引起的运动缺陷无效。已开发出可用于鉴定用于治疗 OIRD 的增强救援剂的方法。类似物 29 在体外和体内具有有效的 MOR 拮抗剂活性，为我们寻找增强的合成阿片类药物拯救剂提供了有希望的线索。1 mg/kg) 对 KOR 激动剂 U50,488 引起的运动缺陷无效。已开发出可用于鉴定用于治疗 OIRD 的增强救援剂的方法。类似物 29 在体外和体内具有有效的 MOR 拮抗剂活性，为我们寻找增强的合成阿片类药物拯救剂提供了有希望的线索。