Center for Drug Evaluation and Research, Food and Drug Administration, United States Department of Health and Human Services, Silver Spring, MD, USA; Department of Pharmacology and Toxicology, Virginia Commonwealth University School of Medicine, Richmond, VA, USA.
Forensic Chemistry Division, Cayman Chemical Company, Ann Arbor, MI, USA.
Pharmacol Biochem Behav. 2023 May;226:173572. doi: 10.1016/j.pbb.2023.173572. Epub 2023 May 24.
Opioid overdoses, particularly those involving fentanyl-related substances (FRS), present a significant public health challenge in the United States. This structure-activity relationship (SAR) study evaluated the relationship between the chemical structure of seventeen FRS and their in vivo mu-opioid-receptor (MOR) mediated effects. SAR evaluations included fluorine substitutions on the aniline or phenethyl ring and variations in N-acyl chain length. Adult male Swiss Webster mice were administered fluorinated regioisomers of fentanyl, butyrylfentantyl and valerylfentanyl, and compared to MOR standards including morphine, buprenorphine, and fentanyl to determine if they would elicit prototypical opioid-like effects including hyperlocomotion (open-field test), antinociception (warm-water tail-withdrawal test), and hypoventilation (whole-body plethysmography test). To determine if the MOR was the pharmacological mechanism responsible for these effects, naltrexone or naloxone pretreatments were administered to evaluate their actions on FRS-induced antinociception and hypoventilation. There were three main findings. First, FRS elicited hyperlocomotion, antinociception, and hypoventilation in mice to varying degrees, similar to prototypical MOR standards. Second, the rank order of potencies for hypoventilatory effects of FRS were different for each series including FRS with increasing N-acyl chain length (i.e., acetylfentanyl, fentanyl, butyrylfentanyl, valerylfentanyl, hexanoylfentanyl), phenethyl-fluorinated regioisomers (e.g., 2'-fluorofentanyl, 3'-fluorofentanyl, 4'-fluorofentanyl), and aniline-fluorinated regioisomers (e.g., ortho-fluorofentanyl, meta-fluorofentanyl, para-fluorofentanyl). Third, the degree of separation in potencies observed for the antinociceptive and hypoventilatory effects of these drugs did not always follow that which was observed for their antinociceptive and hyperlocomotor effects. This study clarifies the in vivo activities for these FRS and elucidates a SAR for MOR-mediated effects among structural isomers.
阿片类药物过量，特别是涉及芬太尼相关物质 (FRS) 的药物过量，是美国面临的重大公共卫生挑战。这项构效关系 (SAR) 研究评估了十七种 FRS 的化学结构与其体内μ-阿片受体 (MOR) 介导的作用之间的关系。SAR 评估包括苯胺或苯乙环上的氟取代以及 N-酰基链长的变化。成年雄性瑞士 Webster 小鼠给予氟代芬太尼、丁酰芬太尼和戊酰芬太尼的区域异构体，并与包括吗啡、丁丙诺啡和芬太尼在内的 MOR 标准品进行比较，以确定它们是否会引起典型的阿片样作用，包括过度运动（旷场试验）、镇痛（温水尾部退缩试验）和通气不足（全身 plethysmography 试验）。为了确定 MOR 是否是这些作用的药理学机制，给予纳曲酮或纳洛酮预处理，以评估它们对 FRS 诱导的镇痛和通气不足的作用。主要有三个发现。首先，FRS 在不同程度上在小鼠中引起过度运动、镇痛和通气不足，类似于典型的 MOR 标准品。其次，FRS 对呼吸抑制作用的效力顺序因每个系列而异，包括 N-酰基链长增加的 FRS（即乙酰芬太尼、芬太尼、丁酰芬太尼、戊酰芬太尼、己酰芬太尼）、苯乙胺氟代区域异构体（例如，2'-氟芬太尼、3'-氟芬太尼、4'-氟芬太尼）和苯胺氟代区域异构体（例如，邻氟芬太尼、间氟芬太尼、对氟芬太尼）。第三，这些药物的镇痛和呼吸抑制作用的效力差异程度并不总是与其镇痛和过度运动作用的效力差异程度一致。本研究阐明了这些 FRS 的体内活性，并阐明了 MOR 介导的结构异构体之间的构效关系。
