دورية أكاديمية
أعرض في EDS

The 8-hydroxyquinoline derivative, clioquinol, is an alpha-1 adrenoceptor antagonist.

التفاصيل البيبلوغرافية
العنوان: The 8-hydroxyquinoline derivative, clioquinol, is an alpha-1 adrenoceptor antagonist.
المؤلفون: Betrie AH; Translational Neurodegeneration Laboratory, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia; Translational Cardiovascular and Renal Research Group, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia., Abdul-Ridha A; Drug Discovery Innovation Group, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia., Hartono H; Faculty of Pharmacy and Pharmaceutical Sciences, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia., Chalmers DK; Faculty of Pharmacy and Pharmaceutical Sciences, Monash Institute of Pharmaceutical Sciences, Monash University, Victoria, Australia., Wright CE; Department of Biochemistry and Pharmacology, The University of Melbourne, Victoria, Australia., Scott DJ; Drug Discovery Innovation Group, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia., Angus JA; Department of Biochemistry and Pharmacology, The University of Melbourne, Victoria, Australia., Ayton S; Translational Neurodegeneration Laboratory, Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Victoria, Australia. Electronic address: scott.ayton@florey.edu.au.
المصدر: Biochemical pharmacology [Biochem Pharmacol] 2024 Apr; Vol. 222, pp. 116092. Date of Electronic Publication: 2024 Feb 24.
نوع المنشور: Journal Article
اللغة: English
بيانات الدورية: Publisher: Elsevier Science Country of Publication: England NLM ID: 0101032 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-2968 (Electronic) Linking ISSN: 00062952 NLM ISO Abbreviation: Biochem Pharmacol Subsets: MEDLINE
أسماء مطبوعة: Publication: Oxford : Elsevier Science
Original Publication: Oxford, New York [etc.] Paragamon Press.
مواضيع طبية MeSH: Clioquinol*/pharmacology, Rats ; Humans ; Animals ; Chlorocebus aethiops ; Oxyquinoline ; Receptors, Adrenergic, alpha-1/metabolism ; Ionophores ; Zinc
مستخلص: Clioquinol (5-chloro-7-iodo-8-hydroxyquinoline) is an antimicrobial agent whose actions as a zinc or copper ionophore and an iron chelator revived the interest in similar compounds for the treatment of fungal and bacterial infections, neurodegeneration and cancer. Recently, we reported zinc ionophores, including clioquinol, cause vasorelaxation in isolated arteries through mechanisms that involve sensory nerves, endothelium and vascular smooth muscle. Here, we report that clioquinol also uniquely acts as a competitive alpha-1 (α 1 ) adrenoceptor antagonist. We employed ex vivo functional vascular contraction and pharmacological techniques in rat isolated mesenteric arteries, receptor binding assays using stabilized solubilized α 1 receptor variants, or wild-type human α 1 -adrenoceptors transfected in COS-7 cells (African green monkey kidney fibroblast-like cells), and molecular dynamics homology modelling based on the recently published α 1A adrenoceptor cryo-EM and α 1B crystal structures. At higher concentrations, all ionophores including clioquinol cause a non-competitive antagonism of agonist-mediated contraction due to intracellular zinc delivery, as reported previously. However, at lower concentration ranges, clioquinol has an additional mechanism of competitively inhibiting α 1 -adrenoceptors that contributes to decreasing vascular contractility. Molecular dynamic simulation showed that clioquinol binds stably to the orthosteric binding site (Asp106) of the receptor, confirming the structural basis for competitive α 1 -adrenoceptor antagonism by clioquinol.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier Inc. All rights reserved.)
فهرسة مساهمة: Keywords: Alpha 1 adrenoceptor; Clioquinol; Molecular dynamic simulation; Pharmacology; Vascular contractility; Vasorelaxation; Zinc ionophores
المشرفين على المادة: 7BHQ856EJ5 (Clioquinol)
5UTX5635HP (Oxyquinoline)
0 (Receptors, Adrenergic, alpha-1)
0 (Ionophores)
J41CSQ7QDS (Zinc)
تواريخ الأحداث: Date Created: 20240226 Date Completed: 20240326 Latest Revision: 20240326
رمز التحديث: 20240326
DOI: 10.1016/j.bcp.2024.116092
PMID: 38408679
قاعدة البيانات: MEDLINE
الوصف
تدمد:1873-2968
DOI:10.1016/j.bcp.2024.116092