Towards Multitargeted Ligands as Pain Therapeutics: Dual Ligands of the Cavα2δ-1 Subunit of Voltage-Gated Calcium Channel and the μ-Opioid Receptor

IF 3.6 4区医学 Q2 CHEMISTRY, MEDICINAL

ChemMedChem Pub Date : 2024-01-17 DOI:10.1002/cmdc.202300473

Dr. Anita Wegert, Dr. Menno Monnee, Wouter de Graaf, Frank van Holst, Dr. Giovanni Bolcato, Dr. José Luis Díaz, Albert Dordal, Dr. Enrique Portillo-Salido, Dr. Raquel F. Reinoso, Sandra Yeste, Dr. Antoni Torrens, Dr. Carmen Almansa

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Abstract

The synthesis and pharmacological activity of a new series of dual ligands combining activities towards the α2δ-1 subunit of voltage-gated calcium channels (Ca_vα2δ-1) and the μ-opioid receptor (MOR) as novel pain therapeutics are reported. A careful exploration of the pharmacophores related to both targets, which in principle had few common characteristics, led to the design of novel compounds exhibiting both activities. The construction of the dual ligands started from published Ca_vα2δ-1 ligands, onto which MOR ligand pharmacophoric elements were added. This exercise led to new amino-acidic substances with good affinities on both targets as well as good metabolic and physicochemical profiles and low potential for drug-drug interactions. A representative compound, (2S,4S)-4-(4-chloro-3-(((cis)-4-(dimethylamino)-4-phenylcyclohexyl)methyl)-5-fluorophenoxy)pyrrolidine-2-carboxylic acid, displayed promising analgesic activities in several in vivo pain models as well as a reduced side-effect profile in relation to morphine.

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将多靶点配体作为疼痛治疗药物：电压门控钙通道 Cav α2δ-1亚基和μ-阿片受体的双重配体。

本研究报告了一系列新的双重配体的合成和药理活性，这些配体兼具对电压门控钙通道（Cav α2δ-1）亚基和μ-阿片受体（MOR）的活性，可作为新型疼痛治疗药物。这两个靶点原则上几乎没有共同特征，通过对与这两个靶点相关的药理作用的仔细探索，设计出了同时具有这两种活性的新型化合物。双配体的构建始于已发表的 Cav α2δ-1 配体，并在其上添加了 MOR 配体药效元素。通过这项工作，我们获得了对两个靶点都具有良好亲和力、代谢和理化特性良好、药物间相互作用可能性低的新型氨基酸物质。一个具有代表性的化合物是 (2S,4S)-4-(4-氯-3-(((顺式)-4-(二甲基氨基)-4-苯基环己基)甲基)-5-氟苯氧基)吡咯烷-2-羧酸，它在多个体内疼痛模型中显示出良好的镇痛活性，而且与吗啡相比，副作用更小。

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

ChemMedChem 医学-药学

CiteScore

6.70

自引率

2.90%

发文量

280

审稿时长

1 months

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