Abstract：
2-Benzylbenzimidazole \'nitazene\' opioids are presenting a growing threat to public health. Although various nitazenes were previously studied, systematic comparisons of the effects of different structural modifications to the 2-benzylbenzimidazole core structure on μ-opioid receptor (MOR) activity are limited. Here, we assessed in vitro structure-activity relationships of 9 previously uncharacterized nitazenes alongside known structural analogues. Specifically, we focused on MOR activation by \'ring\' substituted analogues (i.e., N-pyrrolidino and N-piperidinyl modifications), \'desnitazene\' analogues (lacking the 5-nitro group), and N-desethyl analogues. The results from two in vitro MOR activation assays (β-arrestin 2 recruitment and inhibition of cAMP accumulation) showed that \'ring\' modifications overall yield highly active drugs. With the exception of 4\'-OH analogues (which are metabolites), N-pyrrolidino substitutions were generally more favorable for MOR activation than N-piperidine substitutions. Furthermore, removal of the 5-nitro group on the benzimidazole ring consistently caused a pronounced decrease in potency. The N-desethyl modifications showed important MOR activity, and generally resulted in a slightly lowered potency than comparator nitazenes. Intriguingly, N-desethyl isotonitazene was the exception and was consistently more potent than isotonitazene. Complementing the in vitro findings and demonstrating the high harm potential associated with many of these compounds, we describe 85 forensic cases from North America and the United Kingdom involving etodesnitazene, N-desethyl etonitazene, N-desethyl isotonitazene, N-pyrrolidino metonitazene, and N-pyrrolidino protonitazene. The low-to-sub ng/mL blood concentrations observed in most cases underscore the drugs\' high potencies. Taken together, by bridging pharmacology and case data, this study may aid to increase awareness and guide legislative and public health efforts.
摘要：
2-苄基苯并咪唑\'硝基苯\'阿片类药物对公众健康的威胁越来越大。尽管以前研究过各种硝基苯，对2-苄基苯并咪唑核心结构的不同结构修饰对μ阿片受体（MOR）活性的影响的系统比较有限。这里,我们评估了9种先前未表征的硝基苯与已知结构类似物的体外结构-活性关系。具体来说,我们专注于通过“环”取代类似物激活MOR(即，N-吡咯烷基和N-哌啶基修饰），\'去硝基苯\'类似物（缺乏5-硝基），和N-去乙基类似物。来自两个体外MOR激活测定（β-抑制蛋白2募集和cAMP积累的抑制）的结果表明，“环”修饰总体上产生了高活性药物。除4'-OH类似物（代谢物）外，N-吡咯烷基取代通常比N-哌啶取代更有利于MOR活化。此外，苯并咪唑环上5-硝基的去除始终导致效力显着下降。N-去乙基修饰显示出重要的MOR活性,通常导致效价比对比剂硝基苯略低。有趣的是，N-去乙基异氮氮烯是例外，并且始终比异氮氮烯更有效。补充了体外研究结果，并证明了与许多这些化合物相关的高危害潜力，我们描述了来自北美和英国的85个涉及ettodesnitazene的法医案例，N-去乙基依托氮嗪,N-去乙基异氮氮烯，N-吡咯烷基间氮烯，和N-吡咯烷基质子氮烯。在大多数情况下观察到的低至亚ng/mL的血液浓度强调了药物的高效力。一起来看,通过连接药理学和病例数据，这项研究可能有助于提高认识，并指导立法和公共卫生工作。
