Antinociceptive pharmacology of N-[[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 B 1 receptor antagonist

Frank Porreca, Todd W Vanderah, W. Guo, M. Barth, P. Dodey, V. Peyrou, J. M. Luccarini, J. L. Junien, D. Pruneau

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Abstract

The antinociceptive pharmacology of N-[[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 B 1 antagonist, was characterized. LF22-0542 showed high affinity for human and mouse B1 receptors with virtually no affinity for the human B2 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 B1 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 B1 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 Freund's 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, B1 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 B1 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.

Original languageEnglish (US)
Pages (from-to)195-205
Number of pages11
JournalJournal of Pharmacology and Experimental Therapeutics
Volume318
Issue number1
DOIs
StatePublished - 2006

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Bradykinin
Pharmacology
Hypersensitivity
Formaldehyde
Hot Temperature
Touch
Knockout Mice
Acetic Acid
fumarate N-((4-(4,5-dihydro-1H-imidazol-2-yl)phenyl)methyl)-2-(2-(((4-methoxy-2,6-dimethylphenyl) sulfonyl)methylamino)ethoxy)-N-methylacetamide
Pain
Peripheral Nerve Injuries
Nociception
Freund's Adjuvant
Carrageenan
Wounds and Injuries
Neuralgia
G-Protein-Coupled Receptors
Ion Channels
Cell Biology
Enzymes

ASJC Scopus subject areas

  • Pharmacology

Cite this

@article{168bec42c5ee42e4aa017cfdfa0a31a1,
title = "Antinociceptive pharmacology of N-[[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 B 1 receptor antagonist",
abstract = "The antinociceptive pharmacology of N-[[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 B 1 antagonist, was characterized. LF22-0542 showed high affinity for human and mouse B1 receptors with virtually no affinity for the human B2 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 B1 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 B1 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 Freund's 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, B1 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 B1 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.",
author = "Frank Porreca and Vanderah, {Todd W} and W. Guo and M. Barth and P. Dodey and V. Peyrou and Luccarini, {J. M.} and Junien, {J. L.} and D. Pruneau",
year = "2006",
doi = "10.1124/jpet.105.098368",
language = "English (US)",
volume = "318",
pages = "195--205",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
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T1 - Antinociceptive pharmacology of N-[[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 B 1 receptor antagonist

AU - Porreca, Frank

AU - Vanderah, Todd W

AU - Guo, W.

AU - Barth, M.

AU - Dodey, P.

AU - Peyrou, V.

AU - Luccarini, J. M.

AU - Junien, J. L.

AU - Pruneau, D.

PY - 2006

Y1 - 2006

N2 - The antinociceptive pharmacology of N-[[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 B 1 antagonist, was characterized. LF22-0542 showed high affinity for human and mouse B1 receptors with virtually no affinity for the human B2 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 B1 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 B1 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 Freund's 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, B1 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 B1 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.

AB - The antinociceptive pharmacology of N-[[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 B 1 antagonist, was characterized. LF22-0542 showed high affinity for human and mouse B1 receptors with virtually no affinity for the human B2 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 B1 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 B1 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 Freund's 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, B1 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 B1 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.

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