Relief of loperamide-induced constipation by peptidic and small molecule RXFP4 agonists in mice

IF 5.3 2区医学 Q1 PHARMACOLOGY & PHARMACY

Biochemical pharmacology Pub Date : 2025-04-05 DOI:10.1016/j.bcp.2025.116924

Shiyu Yan , Yan Chen , Jiang Wang , Qiuying Wang , Qingtong Zhou , Hong Liu , Ming-Wei Wang , Dehua Yang

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Abstract

Constipation is a common gastrointestinal disorder often treated symptomatically as the existing therapies all have significant side-effects. The relaxin/insulin-like family peptide receptor 4 (RXFP4), a class A G protein-coupled receptor, has emerged as a potential drug target for this indication as it regulates intestinal motility. Here, we investigated the therapeutic effects of both peptidic (insulin-like peptide 5, INSL5) and small molecule (DC591053) RXFP4 agonists on loperamide-induced constipation in mice. Fecal water content, fecal weight, colonic transit time, and serum levels of neurotransmitters such as nitric oxide (NO), serotonin (5-HT), and vasoactive intestinal peptide (VIP) were assessed, in conjunction with the examination of colon tissue histology and expression levels of aquaporin 3 (AQP3), transient receptor potential vanilloid 1 (TRPV1), and calcitonin gene-related peptide (CGRP). It was found that both INSL5 and DC591053 dose-dependently increased fecal water content and weight, accelerated colonic transit, and improved colon morphology in constipated mice, accompanied by the altered expression levels of factors related to constipation. Comparative analysis revealed that while the two agonists produced similar beneficial outcomes, their different chemical nature may affect pharmacokinetics property and receptor engagement. Our results suggest that the activation of RXFP4 presents a novel approach to alleviating constipation.

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来源期刊

Biochemical pharmacology 医学-药学

CiteScore

10.30

自引率

1.70%

发文量

420

审稿时长

17 days

期刊介绍： Biochemical Pharmacology publishes original research findings, Commentaries and review articles related to the elucidation of cellular and tissue function(s) at the biochemical and molecular levels, the modification of cellular phenotype(s) by genetic, transcriptional/translational or drug/compound-induced modifications, as well as the pharmacodynamics and pharmacokinetics of xenobiotics and drugs, the latter including both small molecules and biologics. The journal''s target audience includes scientists engaged in the identification and study of the mechanisms of action of xenobiotics, biologics and drugs and in the drug discovery and development process. All areas of cellular biology and cellular, tissue/organ and whole animal pharmacology fall within the scope of the journal. Drug classes covered include anti-infectives, anti-inflammatory agents, chemotherapeutics, cardiovascular, endocrinological, immunological, metabolic, neurological and psychiatric drugs, as well as research on drug metabolism and kinetics. While medicinal chemistry is a topic of complimentary interest, manuscripts in this area must contain sufficient biological data to characterize pharmacologically the compounds reported. Submissions describing work focused predominately on chemical synthesis and molecular modeling will not be considered for review. While particular emphasis is placed on reporting the results of molecular and biochemical studies, research involving the use of tissue and animal models of human pathophysiology and toxicology is of interest to the extent that it helps define drug mechanisms of action, safety and efficacy.