Discovery of Novel pH-Sensitive μ-Opioid Receptor Agonists as Potent Analgesics with Reduced Side Effects.

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2025-01-28 eCollection Date: 2025-02-13 DOI:10.1021/acsmedchemlett.4c00529

Zhen Wang, Zong-Zheng Li, Xiao-Min Han, Jing Dong, Ming-Yue Yin, Jie Song, Tao Zhuang, Yuan Wang

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引用次数: 0

Abstract

Although μ-opioid receptor (MOR) agonists are the most effective drugs for relieving acute pain, nonselective activation of MOR can also lead to serious side effects. There is an urgent need for novel analgesics that can selectively activate MOR under pathological conditions while avoiding side effects under normal physiological conditions. In this study, a series of pH-sensitive 4-propionamide piperidine derivatives were synthesized and evaluated for their MOR activities and antinociceptive effects. Among them, compound 22 showed high pH sensitivity for MOR with a K _i pH 7.4/K _i pH 6.4 ratio of 6.6. Compound 22 acted as an MOR agonist in the functional test. Compound 22 exhibited good antinociceptive effects in the acetic acid-induced writhing test (ED₅₀ = 1.5 mg/kg) and carrageenan-induced inflammatory pain model (ED₅₀ = 3.3 mg/kg) in mice. Moreover, compound 22 showed reduced side effects when compared to the equianalgesic dose of fentanyl, including physical dependence, hyperlocomotion, and constipation. Compound 22 holds promise as a safe candidate for further development as an analgesic with diminished side effects.

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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.