Inhibition of leukotriene production by N-[4-[4-(diphenylmethyl)-1- piperazinyl]butyl]-3-(6-methyl-3-pyridyl) acrylamide (AL-3264), a new antiallergic agent.
The effects of AL-3264, which exhibits a 5-lipoxygenase (5-LO) inhibiting property by blocking histamine H1-receptors and inhibition of histamine release, were examined on leukotriene (LT) production and LT-mediated responses. AL-3264 (1-30 microM) inhibited the A23,187-induced LT production from human leukocytes with almost the same potency as that of nordihydroguaiaretic acid. AL-3264 (30-100 mg/kg, p.o.) inhibited the antigen-induced LT production in the abdominal cavity of passively sensitized rats; its effect was as potent as that of AA-861, a 5-LO inhibitor. AL-3264 (30 microM) suppressed both the initial and sustained phases of the antigen-induced contractions in isolated trachea from actively sensitized guinea pig. Phenidone (3 microM), a dual inhibitor of 5-LO and cyclooxygenase (CO), suppressed the sustained phase, while indomethacin was without effect on either phase. AL-3264 (40-160 mg/kg, p.o.) suppressed the arachidonic acid-induced ear edema in mice, for which 5-LO inhibitors were effective but antihistamines were not. The anti-edematous effect of AL-3264 (160 mg/kg) was reduced by intradermal administration of LTC4 (0.1 microgram). These results suggest that AL-3264 suppresses LT production in vivo and in vitro by inhibiting 5-LO activity, and this property may contribute to the antiallergic effect of AL-3264.
Ishii
K
K
Department of Pharmacology, Dainippon Pharmaceutical Co., Ltd., Osaka, Japan.
Yakuo
I
I
Motoyoshi
S
S
Nakagawa
H
H
Nakamura
H
H
D000178:Acrylamides / Q000494:pharmacology*; D000328:Adult; D000818:Animals; D016718:Arachidonic Acid; D000001:Calcimycin / Q000494:pharmacology; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003864:Depression, Chemical; D004487:Edema / Q000139:chemically induced / Q000517:prevention & control; D006168:Guinea Pigs; D006634:Histamine H1 Antagonists / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D015289:Leukotrienes / Q000096:biosynthesis*; D016859:Lipoxygenase Inhibitors / Q000494:pharmacology; D008297:Male; D009637:Masoprocol / Q000494:pharmacology; D051379:Mice; D008813:Mice, Inbred ICR; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014132:Trachea / Q000187:drug effects
D000178:Acrylamides; D016861:Cyclooxygenase Inhibitors; D006634:Histamine H1 Antagonists; D015289:Leukotrienes; D016859:Lipoxygenase Inhibitors; D010879:Piperazines; C080363:AL 3264; D016718:Arachidonic Acid; D000001:Calcimycin; D009637:Masoprocol