Pharmacological characterization of the bradykinin B2 receptor antagonist MEN16132 in rat in vitro bioassays.
The pharmacological profile of the bradykinin B(2) receptor antagonist MEN16132 at the rat B(2) receptor has been investigated and compared with that of icatibant (formerly Hoe 140). Antagonist affinity has been measured through radioligand binding experiments with membranes prepared from uterine and airway tissue. MEN16132 inhibited [(3)H]bradykinin binding with subnanomolar affinity (pK(i) values 10.4 and 10.1 in the uterus and airways, respectively), and was about 3-fold less potent than icatibant (pK(i) values 10.9 and 10.5). Antagonist potency has been estimated towards bradykinin-induced contractility of uterine and urinary bladder smooth muscle preparations. In these assays MEN16132 (pK(B): 9.7 both in uterus and bladder) was about 10-fold more potent than icatibant [pK(B): 8.8 in uterus, and pK(B) 8.0 in urinary bladder, as from Meini, S., Patacchini, R., Giuliani, S., Lazzeri, M., Turini, D., Maggi, C.A., Lecci, A., 2000a. Characterization of bradykinin B(2) receptor antagonists in human and rat urinary bladder. Eur. J. Pharmacol. 388, 177-182]. Washout experiments conducted in the uterine preparation indicated for MEN16132 (100 nM) a slower reversibility than icatibant (300 nM).Altogether present results indicate that MEN16132 displays high affinity and potency also for the rat bradykinin B(2) receptor, and thus is suitable for further investigations in pathophysiological models in this species.
Meini
Stefania
S
Menarini Ricerche S.p.A., Department of Pharmacology, via Rismondo 12A, 50131, Florence, Italy. smeini@menarini-ricerche.it
Cucchi
Paola
P
Catalani
Claudio
C
Bellucci
Francesca
F
Giuliani
Sandro
S
Santicioli
Paolo
P
Maggi
Carlo Alberto
CA
D000818:Animals; D001667:Binding, Competitive; D001920:Bradykinin / Q000031:analogs & derivatives / Q000494:pharmacology; D065094:Bradykinin B2 Receptor Antagonists; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000502:physiology; D009297:Nasal Mucosa / Q000187:drug effects / Q000378:metabolism; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013449:Sulfonamides / Q000494:pharmacology*; D001743:Urinary Bladder / Q000187:drug effects / Q000502:physiology; D014599:Uterus / Q000187:drug effects / Q000502:physiology
C506838:(4-amino-5-(4-(4-(2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido)tetrahydro-2H-4-pyranoylcarbonyl)piperazino)-5-oxopentyl)(trimethyl)ammonium; D065094:Bradykinin B2 Receptor Antagonists; D013449:Sulfonamides; C065679:icatibant; D009952:Ornithine; D001920:Bradykinin