Synthesis and Pharmacology of a Morphinan-Derived Dual Mu-Kappa Opioid Receptor Agonist Analgesic.

IF 4.1 3区医学 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY

ACS Chemical Neuroscience Pub Date : 2025-06-26 DOI:10.1021/acschemneuro.5c00312

Balazs R Varga, Rajendra Uprety, Barnali Paul, Alexis Knoll, Nokomis Ramos-Gonzalez, Kevin Appourchaux, Tori Taylor, Bengisu Turgutalp, Ryosuke Shinouchi, Shainnel O Eans, Ashai K Williams, Steven G Vasquez-Grinnell, Saheem Zaidi, Antonina L Nazarova, Andras Varadi, Valerie Le Rouzic, Taylor G Brown, Shani Martinez, Michael Ansonoff, Rebecca Notis Dardashti, Amanda Hunkele, Joan Subrath, Matthew Welch, Jin Xu, Grace C Rossi, John Pintar, Gavril W Pasternak, Vsevolod Katritch, Jay P McLaughlin, Ying Xian Pan, Susruta Majumdar

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引用次数: 0

Abstract

We present the synthesis and pharmacological characterization of 3'-iodobenzoylamido epoxymorphinans, with a saturated ring C and devoid of 14-OH, based on a dihydronormorphine backbone with various N-17 alkyl substitutions. All synthesized compounds were characterized pharmacologically in radioligand binding assays, [³⁵S]GTPγS functional assays, and for antinociception in mice. Among these analogues, MP1202, a pan-opioid receptor analogue, was characterized further in β-arrestin1/2 studies, G-protein recruitment and Gα-subtype profiling, as well as by evaluation of opioid-mediated effects in mice. MP1202 exhibits potent antinociceptive effects in mice without causing typical opioid side effects, such as respiratory depression and physical dependence. However, it displays conditioned place preference and aversion behaviors similar to those of classical mu and kappa agonists.

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吗啡衍生的双Mu-Kappa阿片受体激动剂的合成及药理作用。

我们提出了3'-碘苯甲酰酰胺环氧吗啡酮的合成和药理学性质，具有饱和环C和缺乏14-OH，基于二氢正吗啡骨架与各种N-17烷基取代。所有合成的化合物在放射配体结合试验、[35S] gtp - γ - s功能试验和小鼠抗伤性实验中进行了药理学表征。在这些类似物中，泛阿片受体类似物MP1202在β-arrestin1/2研究、g蛋白募集和g α-亚型分析以及阿片介导的小鼠效应评估中得到了进一步的表征。MP1202在小鼠中表现出强大的抗痛觉作用，而不会引起典型的阿片类药物副作用，如呼吸抑制和身体依赖。然而，它表现出与经典mu和kappa激动剂相似的条件位置偏好和厌恶行为。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

ACS Chemical Neuroscience BIOCHEMISTRY & MOLECULAR BIOLOGY-CHEMISTRY, MEDICINAL

CiteScore

9.20

自引率

4.00%

发文量

323

审稿时长

1 months

期刊介绍： ACS Chemical Neuroscience publishes high-quality research articles and reviews that showcase chemical, quantitative biological, biophysical and bioengineering approaches to the understanding of the nervous system and to the development of new treatments for neurological disorders. Research in the journal focuses on aspects of chemical neurobiology and bio-neurochemistry such as the following: Neurotransmitters and receptors Neuropharmaceuticals and therapeutics Neural development—Plasticity, and degeneration Chemical, physical, and computational methods in neuroscience Neuronal diseases—basis, detection, and treatment Mechanism of aging, learning, memory and behavior Pain and sensory processing Neurotoxins Neuroscience-inspired bioengineering Development of methods in chemical neurobiology Neuroimaging agents and technologies Animal models for central nervous system diseases Behavioral research