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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.
J Pharmacol Exp Ther. 2005 Nov; 315(2):616-23.JP

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+Show Affiliations

Departments of Pharmacology, Menarini Ricerche, Florence, Italy.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

16027229

Citation

Valenti, Claudio, et al. "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." The Journal of Pharmacology and Experimental Therapeutics, vol. 315, no. 2, 2005, pp. 616-23.
Valenti C, Cialdai C, Giuliani S, et al. 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. J Pharmacol Exp Ther. 2005;315(2):616-23.
Valenti, C., Cialdai, C., Giuliani, S., Lecci, A., Tramontana, M., Meini, S., Quartara, L., & Maggi, C. A. (2005). 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. The Journal of Pharmacology and Experimental Therapeutics, 315(2), 616-23.
Valenti C, et al. 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. J Pharmacol Exp Ther. 2005;315(2):616-23. PubMed PMID: 16027229.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Valenti,Claudio, AU - Cialdai,Cecilia, AU - Giuliani,Sandro, AU - Lecci,Alessandro, AU - Tramontana,Manuela, AU - Meini,Stefania, AU - Quartara,Laura, AU - Maggi,Carlo Alberto, Y1 - 2005/07/18/ PY - 2005/7/20/pubmed PY - 2006/1/13/medline PY - 2005/7/20/entrez SP - 616 EP - 23 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 315 IS - 2 N2 - 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. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/16027229/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_ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=16027229 DB - PRIME DP - Unbound Medicine ER -