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.
Porreca
F
F
Department of Pharmacology, University of Arizona, Arizona Health Sciences Center, Tucson, AZ 85724, USA. frankp@u.arizona.edu
Vanderah
T W
TW
Guo
W
W
Barth
M
M
Dodey
P
P
Peyrou
V
V
Luccarini
J M
JM
Junien
J-L
JL
Pruneau
D
D
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