MEN16132, a Novel Potent and Selective Nonpeptide Kinin B₂Receptor 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.

Bradykinin-Induced Lung Inflammation and Bronchoconstriction: Role in Parainfluenze-3 Virus-Induced Inflammation and Airway Hyperreactivity

“…Icatibant (10 M inhalation exposure), however, had no effect. These results are similar to those by Valenti et al (2005), who have shown that MEN16132 is more potent and longer lasting than icatibant in inhibiting bradykinin-induced bronchoconstriction and microvascular leakage in anesthetized guinea pigs. Our result differs from those of Wirth et al (1993), however, who found that both aerosolized and intravenous icatibant inhibited the bronchoconstriction to bradykinin in anesthetized guinea pigs.…”

“…To date, the effects of bradykinin on the airways have been largely examined after intravenous administration, inhalation, or intratracheal administration to anesthetized animals, such as guinea pigs (Ichinose and Barnes, 1990a,b;Wirth et al, 1993;Miura et al, 1994;Sakamoto et al, 1994;Valenti et al, 2005) and rats (Ellis et al, 2004). One study showed that intravenously administered bradykinin caused bronchoconstriction in unanaesthetized guinea pigs (Chodimella et al, 1991).…”

“…Icatibant is a selective peptidic antagonist of B 2 receptors (Leeb-Lundberg et al, 2005), its affinity (pK i ) for displacement of radioligand binding to human B 1 and B 2 receptors expressed in Chinese hamster ovary cells being Ͻ5 and 10.2, respectively (Regoli et al, 1998). Icatibant administered intravenously, intratracheally, or by aerosol has been shown to inhibit bronchoconstriction to intravenously administered bradykinin in anesthetized guinea pigs (Tramontana et al, 2001;Valenti et al, 2005). Inhaled icatibant also inhibited bronchoconstriction and microvascular leakage after inhaled bradykinin in anesthetized guinea pigs (Sakamoto et al, 1994).…”

“…MEN16132 is a nonpeptide-selective antagonist of B 2 kinin receptors, the affinity values (pK i ) of which for B 1 and B 2 receptors are Ͻ5 and 10.5, respectively (Cucchi et al, 2005). MEN16132 has been shown to block bronchoconstriction to intravenous bradykinin in anesthetized guinea pigs (Valenti et al, 2005).…”

Effect of Intra-articular 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 Kinin B2 Receptor Antagonist, on Nociceptive Response in Monosodium Iodoacetate-Induced Experimental Osteoarthritis in Rats

“…The aim of this study was to investigate the efficacy of the novel potent and selective nonpeptide kinin B 2 receptor antagonist MEN16132 (Cucchi et al, 2005;Valenti et al, 2005) in reducing MIA-induced osteoarthritic pain in the knee joint compared with the peptide B 2 receptor antagonist icatibant.…”