Pharmacological profile of MEN91507, a new CysLT(1) receptor antagonist.
MEN91507 (8-[2-(E)-[4-[4-(4-fluorophenyl)butyloxy]phenyl]vinyl]-4-oxo-2-(5-1H-tetrazolyl)-4H-1-benzopyran sodium salt)) potently displaced [3H]leukotriene D(4) binding from guinea-pig lung and dimethylsulphoxide-differentiated U937 (dU937) cell membranes (K(i) 0.50 +/- 0.16 and 0.65 +/- 0.29 nM, respectively). On the other hand, MEN91507 did not display significant binding affinity for a series of receptors or channels. In functional studies on dU937 cells, MEN91507 behaved as insurmountable antagonist of leukotriene D(4)-induced calcium transients, with an apparent pK(B) of 10.25 +/- 0.15. In anaesthetized guinea-pigs, MEN91507 antagonized in a dose-dependent manner leukotriene D(4)-induced bronchoconstriction following i.v. or oral administration: the ED(50s) were 3.0 +/- 0.3 and 140 +/- 90 nmol/kg, respectively. The inhibition of leukotriene D(4)-induced bronchoconstriction by MEN91507 was long-lasting, since a dose of 0.6 micromol/kg produced 74% reduction of the response after 8 h from administration. Likewise, leukotriene D(4)-induced microvascular leakage was antagonized by MEN91507 either following i.v. or oral administration: a significant inhibitory effect was still evident at 16 h from oral administration of a dose of 6 micromol/kg. It is concluded that MEN91507 is a potent and selective antagonist of both guinea-pig and human CysLT(1) receptors; in addition, in vivo studies on guinea-pigs indicate that MEN91507 is an orally available and long-lasting antagonist of the bronchomotor and pro-inflammatory effects induced by leukotriene D(4) through the stimulation of CysLT(1) receptors.
Cabré
Francesc
F
Menarini Research, Alfonso XII 587, 08918 Badalona, Barcelona, Spain.
Carabaza
Assumpta
A
García
Ana Maria
AM
Calvo
Lidia
L
Cucchi
Paola
P
Palomer
Albert
A
Pascual
Jaume
J
García
Maria Lluisa
ML
Manzini
Stefano
S
Lecci
Alessandro
A
Crea
Attilio
A
Maggi
Carlo Alberto
CA
D000284:Administration, Oral; D000818:Animals; D001578:Benzopyrans / Q000037:antagonists & inhibitors*; D001667:Binding, Competitive; D016084:Bronchoconstriction / Q000187:drug effects; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D004347:Drug Interactions; D006168:Guinea Pigs; D006801:Humans; D007275:Injections, Intravenous; D020024:Leukotriene Antagonists; D015289:Leukotrienes / Q000378:metabolism*; D008168:Lung / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D018077:Receptors, Leukotriene; D013777:Tetrazoles / Q000037:antagonists & inhibitors*
D001578:Benzopyrans; D020024:Leukotriene Antagonists; D015289:Leukotrienes; C471346:MEN91507; D008565:Membrane Proteins; D018077:Receptors, Leukotriene; D013777:Tetrazoles; C412375:cysteinyl leukotriene receptor 2; C083169:leukotriene D4 receptor