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Rupatadine, a new potent, orally active dual antagonist of histamine and platelet-activating factor (PAF).
J Pharmacol Exp Ther. 1997 Jan; 280(1):114-21.JP

Abstract

Rupatadine (UR-12592, 8-chloro-6, 11-dihydro-11-[1-[(5-methyl3-pyridinyl) methyl]-4-piperidinylidene]-5H-benzo[5,6]-cyclohepta[1,2b]pyridine) is a novel compound that inhibits both platelet-activating factor (PAF) and histamine (H1) effects through its interaction with specific receptors (Ki(app) values against [3H]WEB-2086 binding to rabbit platelet membranes and [3H]-pyrilamine binding to guinea pig cerebellum membranes were 0.55 and 0.10 microM, respectively). Rupatadine competitively inhibited histamine-induced guinea pig ileum contraction (pA2 = 9.29 +/- 0.06) without affecting contraction induced by ACh, serotonin or leukotriene D4 (LTD4). It also competitively inhibited PAF-induced platelet aggregation in washed rabbit platelets (WRP) (pA2 = 6.68 +/- 0.08) and in human platelet-rich plasma (HPRP) (IC50 = 0.68 microM), while not affecting ADP- or arachidonic acid-induced platelet aggregation. Rupatadine blocked histamine- and PAF-induced effects in vivo, such as hypotension in rats (ID50 = 1.4 and 0.44 mg/kg i.v., respectively) and bronchoconstriction in guinea pigs (ID50 = 113 and 9.6 micrograms/kg i.v.). Moreover, it potently inhibited PAF-induced mortality in mice (ID50 = 0.31 and 3.0 mg/kg i.v. and p.o., respectively) and endotoxin-induced mortality in mice and rats (ID50 = 1.6 and 0.66 mg/kg i.v.). Rupatadine's duration of action was long, as assessed by the histamine- and PAF-induced increase in vascular permeability test in dogs (42 and 34% inhibition at 26 h after 1 mg/kg p.o.). Rupatadine at a dose of 100 mg/kg p.o. neither modified spontaneous motor activity nor prolonged barbiturate-sleeping time in mice, which indicates a lack of sedative effects. Overall, rupatadine combines histamine and PAF antagonist activities in vivo with high potency, the antihistamine properties being similar to or higher than those of loratadine, whereas rupatadine's PAF antagonist effects were near those of WEB-2066. Rupatadine is therefore a good candidate for further development in the treatment of allergic and inflammatory conditions in which both PAF and histamine are implicated.

Authors+Show Affiliations

Department of Pharmacology, Research Center, J. Uriach & Cía, Barcelona, Spain.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

Language

eng

PubMed ID

8996188

Citation

Merlos, M, et al. "Rupatadine, a New Potent, Orally Active Dual Antagonist of Histamine and Platelet-activating Factor (PAF)." The Journal of Pharmacology and Experimental Therapeutics, vol. 280, no. 1, 1997, pp. 114-21.
Merlos M, Giral M, Balsa D, et al. Rupatadine, a new potent, orally active dual antagonist of histamine and platelet-activating factor (PAF). J Pharmacol Exp Ther. 1997;280(1):114-21.
Merlos, M., Giral, M., Balsa, D., Ferrando, R., Queralt, M., Puigdemont, A., García-Rafanell, J., & Forn, J. (1997). Rupatadine, a new potent, orally active dual antagonist of histamine and platelet-activating factor (PAF). The Journal of Pharmacology and Experimental Therapeutics, 280(1), 114-21.
Merlos M, et al. Rupatadine, a New Potent, Orally Active Dual Antagonist of Histamine and Platelet-activating Factor (PAF). J Pharmacol Exp Ther. 1997;280(1):114-21. PubMed PMID: 8996188.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Rupatadine, a new potent, orally active dual antagonist of histamine and platelet-activating factor (PAF). AU - Merlos,M, AU - Giral,M, AU - Balsa,D, AU - Ferrando,R, AU - Queralt,M, AU - Puigdemont,A, AU - García-Rafanell,J, AU - Forn,J, PY - 1997/1/1/pubmed PY - 1997/1/1/medline PY - 1997/1/1/entrez SP - 114 EP - 21 JF - The Journal of pharmacology and experimental therapeutics JO - J Pharmacol Exp Ther VL - 280 IS - 1 N2 - Rupatadine (UR-12592, 8-chloro-6, 11-dihydro-11-[1-[(5-methyl3-pyridinyl) methyl]-4-piperidinylidene]-5H-benzo[5,6]-cyclohepta[1,2b]pyridine) is a novel compound that inhibits both platelet-activating factor (PAF) and histamine (H1) effects through its interaction with specific receptors (Ki(app) values against [3H]WEB-2086 binding to rabbit platelet membranes and [3H]-pyrilamine binding to guinea pig cerebellum membranes were 0.55 and 0.10 microM, respectively). Rupatadine competitively inhibited histamine-induced guinea pig ileum contraction (pA2 = 9.29 +/- 0.06) without affecting contraction induced by ACh, serotonin or leukotriene D4 (LTD4). It also competitively inhibited PAF-induced platelet aggregation in washed rabbit platelets (WRP) (pA2 = 6.68 +/- 0.08) and in human platelet-rich plasma (HPRP) (IC50 = 0.68 microM), while not affecting ADP- or arachidonic acid-induced platelet aggregation. Rupatadine blocked histamine- and PAF-induced effects in vivo, such as hypotension in rats (ID50 = 1.4 and 0.44 mg/kg i.v., respectively) and bronchoconstriction in guinea pigs (ID50 = 113 and 9.6 micrograms/kg i.v.). Moreover, it potently inhibited PAF-induced mortality in mice (ID50 = 0.31 and 3.0 mg/kg i.v. and p.o., respectively) and endotoxin-induced mortality in mice and rats (ID50 = 1.6 and 0.66 mg/kg i.v.). Rupatadine's duration of action was long, as assessed by the histamine- and PAF-induced increase in vascular permeability test in dogs (42 and 34% inhibition at 26 h after 1 mg/kg p.o.). Rupatadine at a dose of 100 mg/kg p.o. neither modified spontaneous motor activity nor prolonged barbiturate-sleeping time in mice, which indicates a lack of sedative effects. Overall, rupatadine combines histamine and PAF antagonist activities in vivo with high potency, the antihistamine properties being similar to or higher than those of loratadine, whereas rupatadine's PAF antagonist effects were near those of WEB-2066. Rupatadine is therefore a good candidate for further development in the treatment of allergic and inflammatory conditions in which both PAF and histamine are implicated. SN - 0022-3565 UR - https://www.unboundmedicine.com/medline/citation/8996188/Rupatadine_a_new_potent_orally_active_dual_antagonist_of_histamine_and_platelet_activating_factor__PAF__ L2 - https://jpet.aspetjournals.org/cgi/pmidlookup?view=long&pmid=8996188 DB - PRIME DP - Unbound Medicine ER -