PHARMACOLOGICAL PROFILE OF SK-AND-F-104353 - A NOVEL, POTENT AND SELECTIVE PEPTIDOLEUKOTRIENE RECEPTOR ANTAGONIST IN GUINEA-PIG AND HUMAN AIRWAYS

  • 1 November 1987
    • journal article
    • research article
    • Vol. 243  (2) , 474-481
Abstract
In this report, we describe the in vitro and in vivo pharmacologic profile of z(S)-hydroxy-3(R)-[(2-carboxyethyl)thio]-3-[2-(8-phenylocytyl)phenyl]-propanoic acid (SK and F 104353) in guinea pig and human airways. In the isolated guinea pig trachea, SK and F 104353 was a potent, competitive antagonist of leukotriene (LT) D4-induced contractions (pA2 = 8.6). In contrast, SK and 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 and F 104353 (pKB >8.9). SK and F 104353 (10 .mu.M) 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 and F 104353 (30 .mu.M) did not inhibit cyclic nucleotide phosphodiesterase activity measured in homogenates from canine tracheal smooth muscle. In the isolated human bronchus, SK and 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 and F 104353 was also an effective antagonist of LTE4-induced responses in human bronchus (pKB > 8.2). In actively sensitized guinea pig trachea and passively sensitized human bronchus, SK and F 104353 (1 or 10 .mu.M) partially suppressed the secondary, sustained phase of the contractile response to antigen challenge but was without effect on the initial phase. In guinea pig trachea, but not human bronchus, the initial phase of the antigen-induced contraction was inhibited by the H1-histamine receptor antagonists, temelastine (SK and F 93944; 1 .mu.M) or mepyramine (10 .mu.M). A combination of SK and F 104353 and either H1-histamine receptor antagonist markedly reduced or abolished the antigen-induced contractions in both sets of preparations. In anesthetized guinea pigs, pretreatment with aerosolized SK and F 104353 produced substantial inhibition of the bronchospasm elicited by aerosolized LTD4. The results indicate that SK and F 104353 is a potent, selective and competitive LT receptor antagonist in guinea pig and human airways that is efficacious in vitro and in vivo. This compound may be beneficial in the therapy of asthma and other pathophysiologic conditions in which the LTs are thought to be intimately involved.