BAY u9773, a novel antagonist of cysteinyl-leukotrienes with activity against two receptor subtypes.
The effects of BAY u9773 (6(R)-(4'-carboxyphenylthio)-5(S)-hydroxy-7(E),9(E), 11(Z),14(Z)-eicosatetraenoic acid), a cysteinyl-leukotriene analogue, were investigated on a variety of smooth muscle preparations in order to determine its profile as a cysteinyl-leukotriene receptor antagonist. The tissues were contracted with leukotriene C4 or leukotriene D4 and their receptor characteristics defined as either 'typical' or 'atypical' according to the activity or inactivity, respectively, of the selective antagonists ICI 198615, MK 571 and SKF 104353. BAY u9773 antagonised 'typical' cysteinyl-leukotriene receptors with pA2 (or pKB) values in the range 6.8-7.4 and also antagonised 'atypical' receptors with pA2 values in the range 6.8-7.7. However, BAY u9773 had no effect at 10(-6) M against a selection of non-leukotriene stimuli in the same preparations. BAY u9773 competitively displaced [3H]leukotriene D4 binding to guinea-pig lung homogenate, with a pKi of 7.0 +/- 0.1. In the guinea-pig lung strip, BAY u9773 was found to be inactive at 10(-6)M against leukotriene C4- and leukotriene D4-induced contractions, which may suggest the existence of a third type of cysteinyl-leukotriene receptor. These data demonstrate that BAY u9773 is a selective cysteinyl-leukotriene receptor antagonist with comparable activity at both 'typical' and 'atypical' receptors and as such represents a valuable tool for the study of cysteinyl-leukotriene receptors.
Tudhope
S R
SR
Bayer plc, Stoke Poges, UK.
Cuthbert
N J
NJ
Abram
T S
TS
Jennings
M A
MA
Maxey
R J
RJ
Thompson
A M
AM
Norman
P
P
Gardiner
P J
PJ
D000818:Animals; D001667:Binding, Competitive; D001980:Bronchi / Q000187:drug effects / Q000378:metabolism; D003998:Dicarboxylic Acids / Q000494:pharmacology; D005289:Ferrets; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007191:Indazoles / Q000494:pharmacology; D017997:Leukotriene C4 / Q000378:metabolism / Q000494:pharmacology; D017998:Leukotriene D4 / Q000378:metabolism / Q000494:pharmacology; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009126:Muscle Relaxation / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects*; D011422:Propionates / Q000494:pharmacology; D011804:Quinolines / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors; D013189:SRS-A / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D012756:Sheep; D013154:Spleen / Q000187:drug effects / Q000378:metabolism; D014132:Trachea / Q000187:drug effects / Q000378:metabolism
C071435:BAY u9773; D003998:Dicarboxylic Acids; D007191:Indazoles; D011422:Propionates; D011804:Quinolines; D011971:Receptors, Immunologic; D013189:SRS-A; C054217:ICI 198615; D017997:Leukotriene C4; C059141:verlukast; D017998:Leukotriene D4; C052393:pobilukast