title: MEN16132, a novel potent and selective nonpeptide kinin B2 receptor antagonist: in vivo activity on bradykinin-induced bronchoconstriction and nasal mucosa microvascular leakage in anesthetized guinea pigs.
abstract: We have tested the activity of 4-(S)-amino-5-(4-[4-[2,4-dichloro-3-(2,4-dimethyl-8-quinolyloxymethyl)phenylsulfonamido]-tetrahydro-2H-4-pyranylcarbonyl] piperazino)-5-oxopentyl](trimethyl)ammonium chloride hydrochloride (MEN16132), a novel nonpeptide kinin B(2) receptor antagonist, on bradykinin (BK)-induced inflammatory responses, bronchoconstriction, and hypotension in guinea pigs. After i.v. (1-10 nmol/kg i.v.), intratracheal (i.t.) (10-100 nmol/kg i.t.), or aerosol (0.01-0.1 mM/5 min) administration, MEN16132 inhibited in a dose-dependent manner the bronchoconstriction induced by BK (10 nmol/kg i.v.). MEN16132 was more potent and possessed a longer duration of action as compared with the peptide B(2) receptor antagonist icatibant (HOE140; H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH trifluoroacetate). After i.v. administration, its inhibitory effect on bronchoconstriction lasted more than 8 h at 30 nmol/kg. When administered by i.v. or i.t. routes, the dose completely inhibiting bronchoconstriction also partially reduced the hypotensive response to BK, whereas after aerosol administration, the inhibitory effect was limited to respiratory level. Intranasal (i.n.) administration of MEN16132 (0.01-0.3 nmol/nostril) reduced, in a dose-dependent and long-lasting manner, the nasal mucosa plasma protein extravasation induced by BK (100 nmol/nostril), and it exerted a complete inhibition at about 30-fold lower dose than icatibant. At 1 nmol/nostril, MEN16132 activity was significant for at least 6 h with no systemic effect measured as inhibition of BK-induced hypotension, and at 10 nmol/nostril, the inhibitory effect lasted for more than 15 h with only a weak effect on hypotension. These findings indicate that in vivo MEN16132 is a potent kinin B(2) receptor antagonist with long duration of action, both after i.v. and local administration. A complete and prolonged inhibition of BK-induced bronchoconstriction or nasal inflammation can be achieved with MEN16132 topical administration (aerosol or i.n.) at doses devoid of systemic effects.
authors: Departments of Pharmacology, Menarini Ricerche, Florence, Italy.
authors: Claudio
authors: C
authors: Valenti
authors: Cecilia
authors: C
authors: Cialdai
authors: Sandro
authors: S
authors: Giuliani
authors: Alessandro
authors: A
authors: Lecci
authors: Manuela
authors: M
authors: Tramontana
authors: Stefania
authors: S
authors: Meini
authors: Laura
authors: L
authors: Quartara
authors: Carlo Alberto
authors: CA
authors: Maggi
mesh_terms: D000758:Anesthesia; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001798:Blood Proteins / Q000378:metabolism; D001920:Bradykinin / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D065094:Bradykinin B2 Receptor Antagonists; D016084:Bronchoconstriction / Q000187:drug effects*; D002199:Capillary Permeability / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D007022:Hypotension / Q000139:chemically induced / Q000188:drug therapy; D066298:In Vitro Techniques; D007275:Injections, Intravenous; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D009297:Nasal Mucosa / Q000098:blood supply*; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology*
chemical_list: 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; D001798:Blood Proteins; D065094:Bradykinin B2 Receptor Antagonists; D013449:Sulfonamides; C065679:icatibant; D009952:Ornithine; D001920:Bradykinin