Pharmacological evaluation and forensic case series of N-pyrrolidino etonitazene (etonitazepyne), a newly emerging 2-benzylbenzimidazole 'nitazene' synthetic opioid
Pharmacological evaluation and forensic case series of N-pyrrolidino etonitazene (etonitazepyne), a newly emerging 2-benzylbenzimidazole 'nitazene' synthetic opioid
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DOI：
10.1007/s00204-022-03276-4
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发表时间：
2022-04-28
影响因子：
6.1
通讯作者：
Stove, Christophe P.
中科院分区：
文献类型：
--
作者：
Vandeputte, Marthe M.;Krotulski, Alex J.;Stove, Christophe P.
新型合成类阿片继续出现在全世界的娱乐性药物市场上。为了响应对芬太尼类似物的立法禁令，非芬太尼结构模板，如2-苄基苯并咪唑（“硝氮”），正被用于产生新的μ-阿片受体（莫尔）激动剂。在这里，我们使用体外和体内方法，对一种新兴的环状类似物etonitazene进行了表征，称为N-吡咯烷基etonitazene（etonitazepyne）。描述了一系列经分析确认的死亡事件，以补充临床前发现。大鼠脑组织放射性配体结合试验表明，N-吡咯烷基依托硝唑对莫尔受体（Ki = 4.09 nM）的亲和力高于δ-阿片受体（Ki = 959 nM）和κ-阿片受体（Ki = 980 nM）。在MOR-β-arrestin 2激活试验中，N-吡咯烷基依托硝唑显示出高效力（EC 50 = 0.348 nM），与依托硝唑（EC 50 = 0.360 nM）相似，并且大大超过芬太尼（EC 50 = 14.9 nM）和吗啡（EC 50 = 290 nM）的效力。当s.c.对雄性Sprague道利大鼠，N-吡咯烷基依托尼氮诱导阿片样抗伤害、僵硬和热效应。其在热板试验中的效力（ED 50 = 0.0017 mg/kg）分别是芬太尼（ED 50 = 0.0209 mg/kg）和吗啡（ED 50 =3.940 mg/kg）的10倍和2，000倍。发现21例与N-吡咯烷基依托尼嗪相关的过量死亡病例中该药物的血液浓度较低（中位数= 2.2 ng/mL），通常在多物质使用的情况下。据报告，N-吡咯烷基依托硝唑是至少两例病例的死因，证明对人体具有毒性。我们证明，N-吡咯烷基依托硝唑是一种非常有效的莫尔激动剂，可能会给使用者带来高风险。需要继续保持警惕，以识别和表征市场上出现的2-苄基苯并咪唑和其他非芬太尼阿片类药物。
Novel synthetic opioids continue to emerge on recreational drug markets worldwide. In response to legislative bans on fentanyl analogues, non-fentanyl structural templates, such as 2-benzylbenzimidazoles ('nitazenes' ), are being exploited to create new mu-opioid receptor (MOR) agonists. Here, we pharmacologically characterize an emerging cyclic analogue of etonitazene, called N-pyrrolidino etonitazene (etonitazepyne), using in vitro and in vivo methods. A series of analytically confirmed fatalities is described to complement preclinical findings. Radioligand binding assays in rat brain tissue revealed that N-pyrrolidino etonitazene has high affinity for MOR (Ki = 4.09 nM) over delta-opioid (Ki = 959 nM) and kappa-opioid (Ki = 980 nM) receptors. In a MOR-beta-arrestin2 activation assay, N-pyrrolidino etonitazene displayed high potency (EC50 = 0.348 nM), similar to etonitazene (EC50 = 0.360 nM), and largely exceeding the potencies of fentanyl (EC50 = 14.9 nM) and morphine (EC50 = 290 nM). When administered s.c. to male Sprague Dawley rats, N-pyrrolidino etonitazene induced opioid-like antino-ciceptive, cataleptic, and thermic effects. Its potency in the hot plate test (ED50 = 0.0017 mg/kg) was tenfold and 2,000-fold greater than fentanyl (ED50 = 0.0209 mg/kg) and morphine (ED50 =3.940 mg/kg), respectively. Twenty-one overdose fatalities associated with N-pyrrolidino etonitazene were found to contain low blood concentrations of the drug (median = 2.2 ng/mL), commonly in the context of polysubstance use. N-Pyrrolidino etonitazene was reported as a cause of death in at least two cases, demonstrating toxicity in humans. We demonstrate that N-pyrrolidino etonitazene is an extremely potent MOR agonist that is likely to present high risk to users. Continued vigilance is required to identify and characterize emergent 2-benzylbenzimidazoles, and other non-fentanyl opioids, as they appear in the marketplace.