Pharmacologic Profile of SK&F 104353: a Novel, Potent and Selective Peptidoleukotriene Receptor Antagonist in Guinea Pig and Human Airways

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)