3,7-Dihydro-7-[2-hydroxy-3-[4-[3-(phenylthio) propyl]-1-piperazinyl]propyl]-1,3-dimethyl-1H-
purine-2,6-dione dihydrochloride (tazifylline, RS-49014) potently inhibited contractions evoked by stimulation of
histamine H1-receptors in isolated guinea pig ilea and exhibited high affinity for these receptors in radioligand binding studies in vitro. In rats, guinea pigs and dogs the antihistaminic effect of
tazifylline was rapid in onset and long-lived. In anesthetized guinea pigs,
tazifylline markedly inhibited
histamine-induced bronchoconstriction and protected conscious animals from the lethal effect of large doses of the
amine. In conscious rats,
tazifylline was more potent in reducing the inflammatory effects of intradermal
histamine than that evoked by
anaphylactic reaction. In conscious dogs, orally administered
tazifylline inhibited
histamine-induced skin
inflammation for long periods of time and in anesthetized animals attenuated that portion of the
histamine-evoked
hypotension attributable to stimulation of H1-receptors. Results obtained from a variety of in vitro and in vivo experimental preparations showed that
tazifylline had much lower affinity for
histamine H2-receptors, alpha- and beta-
adrenoceptors,
5-hydroxytryptamine and
muscarinic receptor subtypes.
Tazifylline poorly inhibited the release of
histamine from rat peritoneal mast cells. Large oral doses of
tazifylline did not reduce spontaneous locomotor activity in mice, nor did they produce overt symptoms of behavioral depression in conscious rats. Therefore,
tazifylline is a potent, selective and long-acting
histamine H1-receptor antagonist that does not appear to produce central depression in animals.