Received for publication May 9, 2005.
Revised July 13, 2005.
Accepted for publication July 14, 2005.

MEN16132, a novel potent and selective non-peptide 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 MEN16132 or 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, a novel non-peptide kinin B₂ receptor antagonist, on BK-induced inflammatory responses, bronchoconstriction and hypotension in guinea-pigs. After intravenous (1-10 nmol/kg i.v.), intratracheal (10-100 nmol/kg i.t.) or aerosol (0.01-0.1 mM/5min) 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 to the peptide B₂ receptor antagonist Icatibant: after i.v. administration its inhibitory effect on bronchoconstriction lasted more than 8h at 30nmol/kg. When administered by i.v. or i.t. routes, the dose completely inhibiting bronchoconstriction, partially reduced also 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 (PPE) induced by BK (100 nmol/nostril) and it exerted a complete inhibition at about thirty fold lower dose than Icatibant. At 1 nmol/nostril MEN16132 activity was significant for at least 6h with no systemic effect measured as inhibition of BK-induced hypotension and at 10 nmol/nostril the inhibitory effect lasted for more than 15h with only a weak effect on hypotension. These findings indicate that in vivo MEN16132 is a potent kinin B₂ 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.

Key words: B2 receptor antagonist, MEN16132, airways, bradykinin, bronchoconstriction, nasal inflammation