Antinociceptive Pharmacology ofN-[[4-(4,5-Dihydro-1H-imidazol-2-yl)phenyl]methyl]-2-[2-[[(4-methoxy-2,6-dimethylphenyl) sulfonyl]methylamino]ethoxy]-N-methylacetamide, Fumarate (LF22-0542), a Novel Nonpeptidic Bradykinin B1Receptor Antagonist
| Autor: | M. Barth, V. Peyrou, Frank Porreca, Jean-Louis Junien, Wenhong Guo, P. Dodey, D. Pruneau, Todd W. Vanderah, Jean-Michel Luccarini |
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| Rok vydání: | 2006 |
| Předmět: |
Male
Stereochemistry medicine.drug_class Bradykinin Pharmacology Receptor Bradykinin B1 Cell Line Rats Sprague-Dawley Mice chemistry.chemical_compound Fumarates medicine Animals Humans Rats Wistar Receptor Pain Measurement Mice Knockout Sulfonyl chemistry.chemical_classification Acrylamides Analgesics Dose-Response Relationship Drug Antagonist Receptor antagonist Rats Carrageenan Bradykinin B1 Receptor Antagonists Mice Inbred C57BL Nociception chemistry Neuropathic pain Molecular Medicine |
| Zdroj: | Journal of Pharmacology and Experimental Therapeutics. 318:195-205 |
| ISSN: | 1521-0103 0022-3565 |
| DOI: | 10.1124/jpet.105.098368 |
| Popis: | The antinociceptive pharmacology of N -[[4-(4,5-dihydro-1 H -imidazol-2-yl)phenyl]methyl]-2-[2-[[(4-methoxy-2,6-dimethylphenyl) sulfonyl]methylamino]ethoxy]- N -methylacetamide fumarate (LF22-0542), a novel nonpeptidic B 1 antagonist, was characterized. LF22-0542 showed high affinity for human and mouse B 1 receptors with virtually no affinity for the human B 2 receptor; a selectivity index of at least 4000 times was obtained when LF22-0542 was profiled throughout binding or cell biology assays on 64 other G-protein-coupled receptor, 10 ion channels, and seven enzymes. LF22-0542 was a competitive B 1 receptor antagonist and elicited significant antinociceptive actions in the mouse acetic acid-induced writhing assay, as well as in the second phases of formalin-induced nociception in mice and in both the first and second phases of the formalin response in rats. LF22-0542 was active after s.c. but not p.o. administration. In B 1 receptor knockout (KO) mice, acetic acid and formalin responses were significantly reduced and LF22-0542 had no additional effects in these animals. LF22-0542 alleviated thermal hypersensitivity in both acute (carrageenan) and persistent inflammatory (complete Freund9s adjuvant) pain models in rats. LF22-0542 produced a full reversal of experimental neuropathic thermal hypersensitivity but was inactive in reversing nerve injury-induced tactile hypersensitivity in rats. In agreement with this observation, B 1 KO mice subjected to peripheral nerve injury did not show thermal hypersensitivity but developed nerve injury-induced tactile hypersensitivity normally. The data demonstrate the antihyperalgesic actions of a selective systemically administered B 1 receptor antagonist and suggest the utility of this class of agents for the treatment of inflammatory pain states and for some aspects of neuropathic pain. |
| Databáze: | OpenAIRE |
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