PHARMACOLOGICAL STUDIES ON NEWLY SYNTHESIZED ANTI-ALLERGIC AGENTS, 2-METHYL-3-PIPERIDINO-β-PROPIONAPHTONE HYDROCHLORIDE (KZ-111) AND 3-ISOBUTYRYL-2-ISOPROPYLPYRAZOLE-[1, 5-a] PYRIDINE (KC-404)

Abstract

Effects of 2-methyl-3-piperidino-β-propionaphtone hydrochloride (KZ-111), 3-isobutyryl-2-isopropylpyrazolo-[1, 5-a] pyridine (KC-404) and FPL-55712 on experimental allergic reactions were investigated. Homologous passive cutaneous anaphylaxis (PCA) in rats was clearly inhibited by oral and intravenous administrations of KC-404 and KZ-111. FPL-55712 inhibited the PCA reaction only by intravenous injection, but not by oral administration. Maximum inhibition of the PCA reaction by KC-404 and KZ-111 was obtained by administration of these agents 2 hr prior to challenge. The immunological release of histamine from sensitized rat peritoneal mast cells was inhibited by KZ-111 at a concentration of 10−4 g/ml. KC-404 and FPL-55712 did not inhibit the immunological release of histamine. All three compounds had no effect on the release of histamine from rat peritoneal mast cells and on the generation of SRS from rat polymorphonuclear leucocytes by calcium ionophore A23187. KC-404 and KZ-111 produced a downward displacement of the maximum without a parallel shift in LTD4 induced concentration-response curves of guinea pig ileal and tracheal smooth muscle at concentrations between 10−6 and 10−5 g/ml. FPL-55712 at a concentration of 10−6 g/ml produced a parallel shift of LTD4 induced concentration-response curves to the right in both smooth muscle preparations. The 50% inhibitory concentration to the contraction by LTD4 of each of the three compounds is lower than those of other agonists, histamine, PGF2∞ and BaCl2. KC-404 and KZ-111 inhibited CaCl2-induced contraction in K+-depolarized ileal smooth muscle, but FPL-55712 had no effect on the CaCl2-induced contraction. All three compounds inhibited the Schultz-Dale reaction in guinea pig trachea. Respiratory disorder in guinea pig experimental asthma was inhibited by oral administration of KC-404 and KZ-111, but not by FPL-55712.