Your browser doesn't support javascript.
loading
The 8-hydroxyquinoline derivative, clioquinol, is an alpha-1 adrenoceptor antagonist.
Betrie, Ashenafi H; Abdul-Ridha, Alaa; Hartono, Herodion; Chalmers, David K; Wright, Christine E; Scott, Daniel J; Angus, James A; Ayton, Scott.
Afiliación
  • 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, Australi
  • 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.
Biochem Pharmacol ; 222: 116092, 2024 04.
Article en En | MEDLINE | ID: mdl-38408679
ABSTRACT
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 (α1) adrenoceptor antagonist. We employed ex vivo functional vascular contraction and pharmacological techniques in rat isolated mesenteric arteries, receptor binding assays using stabilized solubilized α1 receptor variants, or wild-type human α1-adrenoceptors transfected in COS-7 cells (African green monkey kidney fibroblast-like cells), and molecular dynamics homology modelling based on the recently published α1A adrenoceptor cryo-EM and α1B 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 α1-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 α1-adrenoceptor antagonism by clioquinol.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Clioquinol Límite: Animals / Humans Idioma: En Revista: Biochem Pharmacol Año: 2024 Tipo del documento: Article Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Clioquinol Límite: Animals / Humans Idioma: En Revista: Biochem Pharmacol Año: 2024 Tipo del documento: Article Pais de publicación: Reino Unido