Jones T R, Zamboni R, Belley M, Champion E, Charette L, Ford-Hutchinson A W, Frenette R, Gauthier J Y, Leger S, Masson P
Department of Pharmacology, Merck Frosst Canada Inc., Pointe Claire - Dorval, Qué., Canada.
Can J Physiol Pharmacol. 1989 Jan;67(1):17-28. doi: 10.1139/y89-004.
L-660,711 (3-(3-(2-(7-chloro-2-quinolinyl)ethenyl)phenyl) ((3-dimethyl amino-3-oxo propyl)thio)methyl)thio)propanoic acid is a potent and selective competitive inhibitor of [3H]leukotriene D4 binding in guinea pig (Ki value, 0.22 nM) and human (Ki value, 2.1 nM) lung membranes but is essentially inactive versus [3H]leukotriene C4 binding (IC50 value in guinea pig lung, 23 microM). Functionally it competitively antagonized contractions of guinea pig trachea and ileum induced by leukotriene (LT) D4 (respective pA2 values, 9.4 and 10.5) and LTE4 (respective pA2 values, 9.1 and 10.4) and contractions of human trachea induced by LTD4 (pA2 value, 8.5). L-660,711 (5.8 x 10(-8)M) antagonized contractions of guinea pig trachea induced by LTC4 in the absence (dose ratio = 28) but not in the presence of 45 mM L-serine borate (dose ratio less than 2). L-660,711 (1.9 x 10(-5)M) did not block contractions of guinea pig trachea induced by histamine, acetylcholine, 5-hydroxytryptamine, PGF2 alpha, U-44069, or PGD2. In the presence of atropine, mepyramine, and indomethacin, L-660,711 (1.9 x 10(-5)M) inhibited a small component of the response to antigen on guinea pig trachea but completely blocked anti-IgE-induced contractions of human trachea. L-660,711 (i.v.) antagonized bronchoconstriction induced in anesthetized guinea pigs by i.v. LTC4, LTD4, and LTE4 but did not block bronchoconstriction to arachidonic acid, U-44069, 5-hydroxytryptamine, histamine, or acetylcholine. Intraduodenal L-660,711 antagonized LTD4 (0.2-12.8 micrograms/kg)-induced bronchoconstriction in guinea pigs, and p.o. L-660,711 blocked LTD4- and Ascaris-induced bronchoconstriction in conscious squirrel monkeys and ovalbumin-induced bronchoconstriction in conscious sensitized rats treated with methysergide (3 micrograms/kg). The pharmacological profile of L-660,711 indicates that it is a potent, selective, orally active leukotriene receptor antagonist which is well suited to determine the role played by LTD4 and LTE4 in asthma and other pathophysiologic conditions.
L-660,711（3-(3-(2-(7-氯-2-喹啉基)乙烯基)phenyl) ((3-二甲基氨基-3-氧代丙基)硫代)甲基)硫代)丙酸是一种强效且选择性的竞争性抑制剂，可抑制豚鼠（Ki值为0.22 nM）和人（Ki值为2.1 nM）肺膜中[3H]白三烯D4的结合，但对[3H]白三烯C4的结合基本无活性（豚鼠肺中的IC50值为23 μM）。在功能上，它竞争性拮抗白三烯（LT）D4（pA2值分别为9.4和10.5）和LTE4（pA2值分别为9.1和10.4）诱导的豚鼠气管和回肠收缩，以及LTD4诱导的人气管收缩（pA2值为8.5）。L-660,711（5.8×10⁻⁸M）在不存在45 mM L-丝氨酸硼酸酯时（剂量比 = 28）可拮抗LTC4诱导的豚鼠气管收缩，但在存在时则不能（剂量比小于2）。L-660,711（1.9×10⁻⁵M）不能阻断组胺、乙酰胆碱、5-羟色胺、PGF2α、U-44069或PGD2诱导的豚鼠气管收缩。在阿托品、美吡拉敏和吲哚美辛存在的情况下，L-660,711（1.9×10⁻⁵M）可抑制豚鼠气管对抗原反应的一小部分，但可完全阻断抗IgE诱导的人气管收缩。L-660,711（静脉注射）可拮抗静脉注射LTC4、LTD4和LTE4在麻醉豚鼠中诱导的支气管收缩，但不能阻断对花生四烯酸、U-44069、5-羟色胺、组胺或乙酰胆碱的支气管收缩。十二指肠内给予L-660,711可拮抗LTD4（0.2 - 12.8微克/千克）在豚鼠中诱导的支气管收缩，口服L-660,711可阻断LTD4和蛔虫诱导的清醒松鼠猴支气管收缩，以及在给予麦角新碱（3微克/千克）的清醒致敏大鼠中卵清蛋白诱导的支气管收缩。L-660,711的药理学特性表明它是一种强效、选择性、口服活性的白三烯受体拮抗剂，非常适合用于确定LTD4和LTE4在哮喘及其他病理生理状况中所起的作用。
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