The pharmacology of N-methyl LTC4; a metabolically stable LTC4-mimetic

Abstract N-methyl LTC 4 (NMLTC 4 ) a synthetic analogue of LTC 4 , has been shown not to be a substrate for γ-glutamyl transpeptidase. NMLTC 4 produced contractions of the guinea pig ileum and trachea with pD 2 values of 7.7 ± 0.12 (n = 6) and 8.1 ± 0.1(n = 6) respectively, compared with values of 9.0 ± 0.1 (n = 5) and 8.0 ± 0.2 (n = 6) for LTC 4 . The concentration-response curve to LTC 4 and NMLTC 4 on ileum was displaced to the right by FPL55712. The corresponding pA 2 values were 6.3 ± 0.3 (n = 10) for LTC 4 and 5.7 ± 0.2 (n = 6) for NMLTC 4 . In the presence of acivicin, a γ-glutamyl transpeptidase inhibitor, the LTC 4 concentration-response curve on trachea was displaced to the left, but the NMLTC 4 curve was unaffected. The comparative potencies in the presence of acivicin on trachea indicate that LTC 4 is approximately 6 time more potent than NMLTC 4 whereas on ileum, in the presence of FPL55712 LTC 4 is approximately 14 time more potent. In-vivo, NMLTC 4 is a weak bronchoconstrictor substance being 20–30 less potent than LTC 4 . However, unlike the in-vitro studies the bronchospasm was significantly reduced by pretreatment with LTD 4 antagonists. NMLTC, administered intravenously produced a pronounced hypertensive effect which appeared to be due to peripheral vasoconstriction.