Jpn. J. Pharmacol. 73 (4), 291-298 (1997)

Studies on the Novel Antiallergic Agent HSR-609: Its Penetration into the Central Nervous System in Mice and Guinea Pigs and Its Selectivity for the Histamine H1-Receptor

Masato Kakiuchi, Tetsuo Ohashi, Keiichi Musoh, Kimio Kawamura, Kouji Morikawa and Hideo Kato

Research and Development Division, Hokuriku Seiyaku Co., Ltd., 37-1-1 Inokuchi, Katsuyama, Fukui 911, Japan

Abstract: We studied the pharmacological characteristics of HSR-609 (3-[4-(8-fluoro-5,11-dihydrobenz[b]oxepino[4,3-b]pyridin-11-ylidene)piperidino]propionic acid dihydrate), a novel amphoteric antiallergic agent, on the central nervous system (CNS). Its selectivity for the histamine H1-receptor and its ability to penetrate into the CNS were compared with those of typical antiallergic agents and the non-amphoteric basic compound PY-608 (8-fluoro-5,11-dihydro-11-(1-methyl-4-piperidylidene)benz[b]oxepino[4,3-b]pyridine), which has a chemical structure similar to that of HSR-609. In the in vitro study, HSR-609 had a high affinity for H1-receptors in the guinea pig cerebral cortex in comparison to affinities for muscarinic and serotonin 5-HT2-receptors in the rat cerebral cortex, while the selectivity of PY-608 for the H1-receptor was low. The inhibitory effects of these antiallergic agents on histamine-induced increase of vascular permeability in mice (ED50) were compared with the displacement of [3H]mepyramine binding to H1-receptors in mouse brain ex vivo (ID50). The ID50/ED50 ratio of HSR-609 was much larger than those of cyproheptadine, ketotifen and PY-608 and larger than those of terfenadine and cetirizine. HSR-609 was found to display selective displacement of the [3H]mepyramine binding to H1-receptors for lung vs cerebral cortex as found with terfenadine in guinea pigs ex vivo. These findings suggest that HSR-609 has high selectivity for the H1-receptor and poor ability to penetrate into the CNS in mice and guinea pigs due to its amphoteric chemical structure.

Keywords: Antiallergic agent, HSR-609, Central nervous system penetration, Histamine H1-receptor, Amphoteric compound

Copyrightę The Japanese Pharmacological Society 1997

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