Design, synthesis, and preliminary evaluation of a potential synthetic opioid rescue agent.
Design, synthesis, and preliminary evaluation of a potential synthetic opioid rescue agent.
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DOI：
10.1186/s12929-021-00758-y
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发表时间：
2021-09-09
影响因子：
11
通讯作者：
Prisinzano TE
中科院分区：
文献类型：
--
作者：
Hedrick SL;Luo D;Kaska S;Niloy KK;Jackson K;Sarma R;Horn J;Baynard C;Leggas M;Butelman ER;Kreek MJ;Prisinzano TE
美国最著名的阿片类止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，并用作麻醉辅助剂。然而，当使用不当时，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，可能需要更大剂量或重复剂量的纳洛酮(由于呼吸抑制的复发)来完全逆转芬太尼引起的呼吸抑制，从而使这种治疗方法变得不够充分。为了应对合成阿片类药物过量的危机，本研究旨在寻找一种对芬太尼和其他合成阿片类药物具有增强疗效的新型阿片类药物逆转剂。采用改良的Forsklin诱导的cAMP蓄积实验，研究了一系列纳曲酮类似物在体外对抗芬太尼效应的能力。选择铅类似物29进行进一步的PK研究，然后在热板法中进行体内药理分析以确定其拮抗阿片类药物诱导的抗伤害作用的能力。已鉴定出一系列有效的MOR拮抗剂，包括高效类似物29(IC50 = 2.06 nM)。后续的PK研究显示，在IP给药后，29人拥有近100%的生物利用度。29种药物的脑内浓度超过了血浆浓度，在小鼠体内的明显终端半衰期为~ 80分钟。在热板法中，29 mg/kg呈剂量依赖性(0.01~0.1 mg/kg；ip)，并完全拮抗羟考酮(5.6 mg/kg；ip)的抗伤害作用。此外，完全有效地预防羟考酮诱导的抗伤害感受的29剂量(0.1 mg/kg)对KOR激动剂U50,488引起的运动障碍无效。已开发的方法可用于识别用于治疗OIRD的增强型救援剂。类似物29在体外和体内都具有很强的吗啡拮抗剂活性，为我们寻找增强的合成阿片类药物救援剂提供了一个有希望的线索。网上版载有补充材料，可在10.1186/s12929-021-00758-y查阅。
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. The online version contains supplementary material available at 10.1186/s12929-021-00758-y.
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影响因子：
7.3
作者：
CHATTERJIE, N;INTURRISI, CE;BLUMBERG, H
通讯作者：
BLUMBERG, H
海洛因，处方阿片类药物和非法芬太尼过量的纳洛酮：挑战和创新对动态流行作出反应。
DOI：
10.1016/j.drugpo.2017.06.005
发表时间：
2017-08
期刊：
The International journal on drug policy
影响因子：
--
作者：
Fairbairn N;Coffin PO;Walley AY
通讯作者：
Walley AY
DOI：
10.1111/j.1476-5381.1967.tb02108.x
发表时间：
1967-01-01
期刊：
BRITISH JOURNAL OF PHARMACOLOGY AND CHEMOTHERAPY
影响因子：
--
作者：
BLANE, GF;BOURA, ALA;LISTER, RE
通讯作者：
LISTER, RE
影响因子：
7.3
作者：
Moynihan, H.;Jales, A. R.;Husbands, S. M.
通讯作者：
Husbands, S. M.
影响因子：
7.3
作者：
Crowley, Rachel Saylor;Riley, Andrew P.;Sherwood, Alexander M.;Groer, Chad E.;Shivaperumal, Nirajmohan;Biscaia, Miguel;Paton, Kelly;Schneider, Sebastian;Provasi, Davide;Kivell, Bronwyn M.;Filizola, Marta;Prisinzano, Thomas E.
通讯作者：
Prisinzano, Thomas E.