Hay D W, Muccitelli R M, Tucker S S, Vickery-Clark L M, Wilson K A, Gleason J G, Hall R F, Wasserman M A, Torphy T J
Department of Pharmacology, Smith Kline & French Laboratories, King of Prussia, Pennsylvania.
J Pharmacol Exp Ther. 1987 Nov;243(2):474-81.
In this report, we describe the in vitro and in vivo pharmacologic profile of 2(S)-hydroxy-3(R)-[(2-carboxyethyl)thio]-3-[2-(8-phenyloctyl)pheny l]- propanoic acid (SK&F 104353) in guinea pig and human airways. In the isolated guinea pig trachea, SK&F 104353 was a potent, competitive antagonist of leukotriene (LT) D4-induced contractions (pA2 = 8.6). In contrast, SK&F 104353 produced little effect on LTC4 concentration-response curves under conditions where the bioconversion of LTC4 to LTD4 was inhibited. LTE4-induced contractions in guinea pig trachea were sensitive to inhibition by SK&F 104353 (pKB greater than 8.9). SK&F 104353 (10 microM) had no intrinsic contractile activity and was without effect on contractions produced by KCl, histamine, prostaglandin D2, platelet-activating factor or U-44069 in guinea pig trachea. Furthermore, unlike other purported LT antagonists, LT 171883 and FPL 55712, SK&F 104353 (30 microM) did not inhibit cyclic nucleotide phosphodiesterase activity measured in homogenates from canine tracheal smooth muscle. In the isolated human bronchus, SK&F 104353 produced concentration-dependent rightward shifts in LTD4 concentration-response curves and, unlike in guinea pig trachea, was an effective antagonist of LTC4-induced contractions with a pKB of 8.0 to 8.4. This provides further evidence that, in contrast to guinea pig airways, responses produced by LTC4 and LTD4 in human bronchus appear to be mediated via the same LT receptor population. SK&F 104353 was also an effective antagonist of LTE4-induced responses in human bronchus (pKB greater than 8.2).(ABSTRACT TRUNCATED AT 250 WORDS)
在本报告中，我们描述了2(S)-羟基-3(R)-[(2-羧乙基)硫代]-3-[2-(8-苯基辛基)苯基]丙酸(SK&F 104353)在豚鼠和人类气道中的体外和体内药理学特征。在离体豚鼠气管中，SK&F 104353是白三烯(LT)D4诱导收缩的强效竞争性拮抗剂(pA2 = 8.6)。相比之下，在LTC4向LTD4的生物转化受到抑制的条件下，SK&F 104353对LTC4浓度-反应曲线几乎没有影响。豚鼠气管中LTE4诱导的收缩对SK&F 104353的抑制敏感(pKB大于8.9)。SK&F 104353(10 microM)没有内在收缩活性，对豚鼠气管中氯化钾、组胺、前列腺素D2、血小板活化因子或U-44069诱导的收缩没有影响。此外，与其他所谓的LT拮抗剂LT 171883和FPL 55712不同，SK&F 104353(30 microM)不抑制犬气管平滑肌匀浆中测得的环核苷酸磷酸二酯酶活性。在离体人支气管中，SK&F 104353使LTD4浓度-反应曲线产生浓度依赖性右移，并且与豚鼠气管不同，它是LTC4诱导收缩的有效拮抗剂，pKB为8.0至8.4。这进一步证明，与豚鼠气道不同，LTC4和LTD4在人支气管中产生的反应似乎是通过相同的LT受体群体介导的。SK&F 104353也是人支气管中LTE4诱导反应的有效拮抗剂(pKB大于8.2)。(摘要截短于250字)
