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 B1 receptor antagonist.
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 B1 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.
Department of Pharmacology, University of Arizona, Arizona Health Sciences Center, Tucson, AZ 85724, USA. frankp@u.arizona.edu
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Porreca
T W
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Vanderah
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Guo
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M
Barth
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Dodey
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Peyrou
J M
JM
Luccarini
J-L
JL
Junien
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Pruneau
D000178:Acrylamides / Q000737:chemistry / Q000494:pharmacology*; D000700:Analgesics / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D065169:Bradykinin B1 Receptor Antagonists; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D005650:Fumarates / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D043783:Receptor, Bradykinin B1 / Q000502:physiology
D000178:Acrylamides; D000700:Analgesics; D065169:Bradykinin B1 Receptor Antagonists; D005650:Fumarates; C512396:N-((4-(4,5-dihydro-1H-imidazol-2-yl)phenyl)methyl)-2-(2-(((4-methoxy-2,6-dimethylphenyl) sulfonyl)methylamino)ethoxy)-N-methylacetamide, fumarate; D043783:Receptor, Bradykinin B1; C032005:fumaric acid