[Antiallergic effects of a novel compound, SWR-00151].
The effects of a newly synthesized compound, SWR-00151 (4-[2-[4-(1H-indol-3-yl)-1-piperidinyl)ethyl]-2(1H)-quinolinone), on experimental Type I allergic models were investigated. Results obtained were as follows: The compound (3 approximately 30 mg/kg, p.o.) dose-dependently inhibited 48-hr passive cutaneous anaphylaxis (PCA) in the rat. From the strong antagonism against the histamine-induced contraction of the isolated guinea pig ileum and the lack of suppressive effect on anaphylactic histamine release from rat peritoneal exudate cells, it is deduced that the compound's inhibitory action against PCA is due to antihistaminic action. Both gamma 1-rich serum- and IgE-rich serum-mediated experimental asthmas in the guinea pig were also considerably inhibited by a small dose (1 mg/kg, p.o.) of the compound. The inhibitory mechanism seems to be almost the same as that of the PCA because the compound did not show any effect on the experimental asthma in guinea pigs pretreated with H1- and H2-antihistaminics. In addition to that, it is well known that the model is largely mediated by anaphylactically released histamine. On the other hand, while ketotifen and oxatomide, which possess potent antihistaminic activity, modestly suppressed a rat experimental asthma SWR-00151 still demonstrated a substantial inhibitory activity, strongly suggesting that histamine does not play an important role in this asthma model. Serotonin was revealed to be partly responsible for the early phase of the reaction by the assessment with methysergide, an antiserotonergic, and SWR-00151 as well as oxatomide and ketotifen showed slight antagonism against serotonin in high concentrations (10(-6) and 10(-5) M) in vitro. When thromboxane (TX) B2 in the plasma was measured during the reaction, significant increased levels of the chemical mediator were found, which were obviously prevented by the treatment with SRW-00151. From these results, SWR-00151 is expected to be a drug effective for the treatment of asthma through mechanisms not only of antihistaminic action but also through inhibition of anaphylactic formation/release of other mediators like TXA2.
Tanaka
Y
Y
Osaka Research Laboratories, Sawai Pharmaceutical CO., Ltd., Osaka, Japan.
Masai
E
E
Yashima
T
T
Furukawa
M
M
D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001249:Asthma / Q000188:drug therapy; D016084:Bronchoconstriction / Q000187:drug effects; D002478:Cells, Cultured; D003864:Depression, Chemical; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006633:Histamine Antagonists; D006636:Histamine Release / Q000187:drug effects; D007082:Ileum / Q000187:drug effects; D066298:In Vitro Techniques; D007665:Ketotifen / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010323:Passive Cutaneous Anaphylaxis / Q000187:drug effects*; D010879:Piperazines / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012702:Serotonin Antagonists
D018926:Anti-Allergic Agents; D006633:Histamine Antagonists; D010879:Piperazines; D015363:Quinolones; C106775:SWR 00151; D012702:Serotonin Antagonists; C015408:oxatomide; D007665:Ketotifen