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.