BACKGROUND Previous studies have reported that benzodiazepines (BZDs) seem to enhance euphoric and reinforcing properties of opioids in opioid users so that a direct effect on opioid receptors has been postulated, together with a possible synergistic induction of severe side effects due to co use of BDZs and opioids. This is particularly worrisome given the appearance on the market of designer benzodiazepines (DBZDs), whose activity/toxicity profiles are scarcely known. OBJECTIVES This study aimed to evaluate, through computational studies, the binding affinity (or lack thereof) of 101 DBZDs identified online on the kappa, mu, and delta opioid receptors (K, M, DOR); and to assess whether their mechanism of action could include activation of the latter. METHODS MOE® was used for the computational studies. Pharmacophore mapping based on strong opioids agonist binders' 3D chemical features was used to filter the DBZDs. Resultant DBZDs were docked into the crystallised 3D active conformation of KOR (PDB6B73), DOR (PDB6PT3) and MOR (PDB5C1M). Co-crystallised ligands and four strong agonists were used as reference compounds. A score (S, Kcal/mol) representative of the predicted binding affinity, and a description of ligand interactions were obtained from MOE®. RESULTS The docking results, filtered for S < -8.0 and the interaction with the Asp residue, identified five DBZDs as putative binders of the three ORs : ciclotizolam, fluloprazolam, JQ1, Ro 48-6791, and Ro 48-8684. CONCLUSION It may be inferred that at least some DBZDs may have the potential to activate opioid receptors. This could mediate/increase their anxiolytic, analgesic, and addiction potentials, as well as worsen the side effects associated with opioid co-use.

中文翻译：

---

设计者苯二氮卓类药物对阿片受体的活性：对接研究。

背景 先前的研究报告称，苯二氮卓类药物 (BZDs) 似乎可以增强阿片类药物使用者的欣快感和强化特性，因此假设对阿片类药物受体有直接影响，同时可能协同诱导由于共同使用 BDZs 而引起的严重副作用和阿片类药物。考虑到设计师苯二氮卓类药物 (DBZD) 在市场上的出现，这一点尤其令人担忧，其活性/毒性特征鲜为人知。目标 本研究旨在通过计算研究评估在线鉴定的 101 种 DBZD 对 kappa、mu 和 delta 阿片受体（K、M、DOR）的结合亲和力（或缺乏结合亲和力）；并评估它们的作用机制是否可以包括激活后者。方法 MOE® 用于计算研究。基于强阿片类激动剂结合剂的 3D 化学特征的药效团映射用于过滤 DBZD。生成的 DBZD 对接到 KOR (PDB6B73)、DOR (PDB6PT3) 和 MOR (PDB5C1M) 的结晶 3D 活性构象中。共结晶的配体和四种强激动剂用作参考化合物。代表预测的结合亲和力的分数（S，Kcal/mol）和配体相互作用的描述从 MOE® 获得。结果 对接结果（针对 S < -8.0 和与 Asp 残基的相互作用进行过滤）确定了五种 DBZD 作为三种 OR 的推定结合剂：环噻唑仑、氟普唑仑、JQ1、Ro 48-6791 和 Ro 48-8684。结论 可以推断，至少有一些二溴苯醚可能具有激活阿片受体的潜力。这可以调解/增加他们的抗焦虑、镇痛、