How Subtle Molecular Differences in the Morphinan Opioid Antagonists Affect Their Physicochemical and In Vitro ADME Properties

IF 3.9 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-10 DOI:10.1021/acsmedchemlett.6c00324

Sigal Saphier, Ada Wenger, Alexander Pevzner, Dina Yeffet, Boris Smolkin, Naama Lifshin-Karton, Shlomi Elias, Yoav Eichen, Galit Parvari, Shahaf Katalan, Yossi Zafrani

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Abstract

Naloxone, naltrexone and nalmefene are closely related morphinan antagonists with comparable affinities to the μ-opioid receptor (MOR) but markedly different pharmacokinetics (PK) and metabolic fate. In this study, we evaluated their pharmacologically-relevant molecular/physicochemical properties, PAMPA-BBB (Parallel Artificial Membrane Permeability Assay for the Blood-Brain Barrier) permeability and in vitro metabolic stability to determine how subtle structural differences influence ADME-relevant properties. Moreover, the pharmacologically-relevant properties of these three antagonists were compared with those of the best-known synthetic opioid agonist, fentanyl. We found that the methyl-cyclopropyl versus allyl head group, as well as the C6-carbonyl versus C6-ethenyl group, dramatically influence all the above-mentioned properties and help explain the in vivo observed differences between these antagonists. These results may support the rational design of new and improved opioid antagonists with optimized PK properties.

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吗啡类阿片拮抗剂的细微分子差异如何影响其理化和体外ADME性能

纳洛酮、纳曲酮和纳美芬是密切相关的吗啡受体拮抗剂，它们对μ-阿片受体（MOR）具有相似的亲和力，但药代动力学（PK）和代谢命运有显著差异。在这项研究中，我们评估了它们的药理学相关的分子/物理化学性质、PAMPA-BBB（平行人工膜透性测定血脑屏障）渗透性和体外代谢稳定性，以确定细微的结构差异如何影响adme相关性质。此外，将这三种拮抗剂的药理学相关特性与最著名的合成阿片受体激动剂芬太尼进行了比较。我们发现甲基-环丙基对烯丙基，以及c6 -羰基对c6 -乙烯基，显著影响上述所有性质，并有助于解释这些拮抗剂在体内观察到的差异。这些结果可能为合理设计具有优化PK性能的新型和改进的类阿片拮抗剂提供支持。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.