Hill R J, Grant A M, Volberg W, Rapp L, Faltynek C, Miller D, Pagani K, Baizman E, Wang S, Guiles J W
Department of Biochemistry, Sanofi Winthrop, Inc., Collegeville, Pennsylvania 19426, USA.
Mol Pharmacol. 1995 Jul;48(1):98-104.
We report the in vitro biological characterization of WIN 17317-3 (1-benzyl-7-chloro-4-n-propylimino-1,4-dihydroquinoline hydrochloride), a novel inhibitor of voltage-activated (n-type) K+ channels in human T lymphocytes. WIN 17317-3 inhibits 125I-charybdotoxin binding to n-type K+ channels with an IC50 value of 83 +/- 4 nM. WIN 17317-3 demonstrates competitive inhibition of 125I-charybdotoxin binding by increasing its dissociation constant without changing the total number of channels bound and by having no effect on its dissociation rate constant. WIN 17317-3 inhibits whole-cell, n-type K+ currents with characteristics indicative of open channel block and has an IC50 value of 335 nM. The compound is 150-fold selective for n-type K+ channels, compared with Ca(2+)-activated, charybdotoxin-sensitive K+ channels in smooth muscle. In purified CD4+ T lymphocytes activated with either anti-CD3 plus phorbol ester or anti-CD3 plus anti-CD28, WIN 17317-3 decreases interleukin-2 production with EC50 values of 0.8 microM and 1 microM, respectively. WIN 17317-3 is a novel, potent, and selective nonpeptide n-type K+ channel antagonist that inhibits interleukin-2 production in human T lymphocytes.
我们报告了WIN 17317-3（1-苄基-7-氯-4-正丙基亚氨基-1,4-二氢喹啉盐酸盐）的体外生物学特性，它是一种新型的人T淋巴细胞电压激活（n型）钾通道抑制剂。WIN 17317-3抑制125I-蝎毒素与n型钾通道的结合，IC50值为83±4 nM。WIN 17317-3通过增加其解离常数而不改变结合通道的总数且对其解离速率常数无影响，表现出对125I-蝎毒素结合的竞争性抑制。WIN 17317-3抑制全细胞n型钾电流，其特征表明为开放通道阻断，IC50值为335 nM。与平滑肌中钙激活的、对蝎毒素敏感的钾通道相比，该化合物对n型钾通道具有150倍的选择性。在用抗CD3加佛波酯或抗CD3加抗CD28激活的纯化CD4+ T淋巴细胞中，WIN 17317-3分别以0.8 microM和1 microM的EC50值降低白细胞介素-2的产生。WIN 17317-3是一种新型、强效且选择性的非肽n型钾通道拮抗剂，可抑制人T淋巴细胞中白细胞介素-2的产生。
