Clioquinol(5-氯-7-碘-8-羟基喹啉)是一种抗菌剂,其作为锌或铜离子载体和铁螯合剂的作用使人们对治疗真菌和细菌感染的类似化合物产生了兴趣。神经变性和癌症。最近,我们报道了锌离子载体,包括Clioquinol,通过涉及感觉神经的机制在孤立的动脉中引起血管舒张,内皮和血管平滑肌。这里,我们报告说,clioquinol也是一种独特的竞争性α-1(α1)受体拮抗剂。我们在大鼠离体肠系膜动脉中采用了离体功能性血管收缩和药理技术,使用稳定的溶解的α1受体变体的受体结合测定,或在COS-7细胞(非洲绿猴肾成纤维细胞样细胞)中转染的野生型人α1-肾上腺素受体,和基于最近发表的α1A肾上腺素受体晶体结构的分子动力学同源性建模。在较高浓度下,所有离子载体,包括氯噻酚,由于细胞内锌传递,引起激动剂介导的收缩的非竞争性拮抗作用,正如之前报道的。然而,在较低的浓度范围内,clioquinol具有竞争性抑制α1-肾上腺素受体的额外机制,有助于降低血管收缩力。分子动力学模拟表明,氯羟基喹啉与受体的正构结合位点(Asp106)稳定结合,确认了氯碘喹啉竞争性α1-肾上腺素受体拮抗作用的结构基础。
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.