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.
