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The pharmacological evaluation of LY170680, a novel leukotriene D 4 and E 4 antagonist in the guinea‐pig
Author(s) -
Boot J.R.,
Bond A.,
Gooderham R.,
O'Brien A.,
Parsons M.,
Thomas K.H.
Publication year - 1989
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.1989.tb16890.x
Subject(s) - leukotriene d4 , antagonist , guinea pig , histamine , ileum , leukotriene , ed50 , acetylcholine , competitive antagonist , chemistry , medicine , endocrinology , pharmacology , in vitro , biology , biochemistry , asthma , receptor
1 This paper describes the evaluation of LY170680 (5‐<3‐[2(R) (carboxyethylthio)‐1(S)‐hydroxypentadeca 3(E)5(Z)‐dienyl]phenyl > 1H tetrazole, as an antagonist of the cysteinyl leukotrienes C 4 , D 4 , E 4 , in a variety of in vitro and in vivo models. 2 In vitro , LY170680 was a potent, selective, and competitive antagonist of LTD 4 , and LTE 4 . It produced a concentration‐dependent rightward displacement of the concentration‐response curves elicited by either LTD 4 or LTE 4 on both the guinea‐pig ileal and tracheal preparation. The pA 2 values for LY170680 were estimated to be 8.1 ± 0.2 ( n = 8) and 8.1 ± 0.1 ( n = 6) on trachea, and 8.7 ± 0.1 ( n = 12) and 9.0 ± 0.3 ( n = 6) on ileum for both LTD 4 and LTE 4 respectively. The slopes of the Schild plots in these studies were all close to unity. 3 LY170680 was shown to be a modest antagonist of the LTC 4 ‐induced responses on guinea‐pig ileum (pA 2 7.0 ± 0.2 n = 5), but had no discernable effects against contractions induced by histamine, prostaglandin E 2 (PGE 2 ), PGF 2α or acetylcholine. The compound also reduced the LTC 4 ‐induced responses on trachea, but in a non competitive manner. 4 Intravenous LY170680 reduced in a dose‐dependent manner (ED 50 3.8 mg kg −1 , 60 min pretreatment) the fall in compliance in the anaesthetized guinea‐pig, and the rise in total pulmonary resistance (TPR) (ED 50 2.0 mg kg −1 , 30min pretreatment) in the artificially ventilated guinea‐pig, produced by intraveous LTD 4 . 5 LY170680 (5 mg kg −1 , i.v.) was also effective in reducing the increase in TPR to intravenous antigen in sensitized animals pretreated with mepyramine, indomethacin and propranolol. 6 The compound was only moderately effective (ED 50 40 mg kg −1 p.o.) in preventing the rise in TPR induced by intravenous LTD 4 , when given orally. 7 Inhaled LY170680 was particularly effective in preventing the increase in TPR produced by an exposure to aerosolised LTD 4 . An estimated 1–2 μg of LY170680 delivered to the airways by nebuliser 1 hour beforehand, produced a 6 fold lateral displacement to the right of the dose‐response curve to LTD 4 . 8 Studies in conscious animals indicated that inhaled LY170680 produced a dose‐dependent reduction in the increased volume of gas, trapped in the lung following exposure to aerosolised LTD 4 . Duration studies also indicated that an estimated inhaled dose of 10 μg LY170680 significantly reduced the LTD 4 ‐induced increase in trapped lung gas volume for at least 4 h. Inhaled LY170680 also reduced LTC 4 ‐induced increase in gas trapping in a manner similar to LTD 4 . However, histamine‐induced gas trapping was unaffected.