Deziel M R, Davis P J, Davis F B, Cody V, Galindo J, Blas S D
Department of Medicine, State University of New York, Buffalo.
Arch Biochem Biophys. 1989 Nov 1;274(2):463-70. doi: 10.1016/0003-9861(89)90459-1.
Benzofurans have important actions on the electrical properties of myocardium; the biochemical basis of those actions is not known. Crystallographic examination of these compounds has revealed that benzofurans share structural homologies with the traditional calmodulin antagonists N-(6-aminohexyl)-5-chloro-1-naphthalene and trifluoperazine. In the present study, the ability of amiodarone, desethylamiodarone, and benziodarone to displace the fluorescent ligand 8-anilino-1-naphthalene sulfonic acid (ANS) from calmodulin, to modulate the fluorescence emission of dansylcalmodulin, and to inhibit the activation by calmodulin of bovine brain cyclic nucleotide phosphodiesterase and human erythrocyte membrane Ca2+-ATPase were investigated at concentrations ranging from 10(-8) to 10(-6) M. These benzofurans displaced ANS from calmodulin with nearly equal efficiency upon forming a 1:1 complex with that protein. Each of these compounds also produced a decreased fluorescence emission of dansylcalmodulin, but with relative efficiencies being desethylamiodarone greater than amiodarone greater than benziodarone. Amiodarone and desethylamiodarone inhibited calmodulin-stimulable phosphodiesterase activity with similar potencies. Amiodarone and benziodarone inhibited calmodulin-stimulable Ca2+-ATPase activity equally, but desethylamiodarone had no effect. The observed differential effects of the amiodarone analogs suggest that calmodulin may possess multiple benzofuran-binding sites that are recognized by specific targets and ligands of this Ca2+-binding protein and that the cellular action of amiodarone and its analogs may reflect calmodulin antagonism.
苯并呋喃对心肌电特性具有重要作用；这些作用的生化基础尚不清楚。对这些化合物的晶体学研究表明，苯并呋喃与传统的钙调蛋白拮抗剂N-(6-氨基己基)-5-氯-1-萘胺和三氟拉嗪具有结构同源性。在本研究中，研究了胺碘酮、去乙基胺碘酮和苄碘达隆在10(-8)至10(-6)M浓度范围内从钙调蛋白上置换荧光配体8-苯胺基-1-萘磺酸(ANS)、调节丹磺酰钙调蛋白荧光发射以及抑制钙调蛋白对牛脑环核苷酸磷酸二酯酶和人红细胞膜Ca2+-ATP酶激活的能力。这些苯并呋喃与钙调蛋白形成1:1复合物后，以几乎相同的效率从钙调蛋白上置换ANS。这些化合物中的每一种还使丹磺酰钙调蛋白的荧光发射降低，但相对效率为去乙基胺碘酮大于胺碘酮大于苄碘达隆。胺碘酮和去乙基胺碘酮以相似的效力抑制钙调蛋白刺激的磷酸二酯酶活性。胺碘酮和苄碘达隆对钙调蛋白刺激的Ca2+-ATP酶活性的抑制作用相同，但去乙基胺碘酮没有作用。胺碘酮类似物观察到的不同效应表明，钙调蛋白可能具有多个苯并呋喃结合位点，这些位点可被这种Ca2+结合蛋白的特定靶标和配体识别，并且胺碘酮及其类似物的细胞作用可能反映钙调蛋白拮抗作用。
