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 H]-Receptor

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We studied the pharmacological characteristics of HSR-609 (3-[4-(8-fluoro-5, 11-dihydrobenz[b]oxepino[4, 3-<I>b</I>]pyridin-11-ylidene)-piperidino]propionic acid dihydrate), a novel amphoteric antiallergic agent, on the central nervous system (CNS). Its selectivity for the histamine H<SUB>1</SUB>-receptor and its ability to penetrate into the CNS were compared with those of typical antiallergic agents and the nonamphoteric basic compound PY-608 (8-fluoro-5, 11-dihydro-11-(1-methyl-4-piperidylidene)benz[<I>b</I>]oxepino[4, 3-<I>b</I>]pyridine), which has a chemical structure similar to that of HSR-609. In the in vitro study, HSR-609 had a high affinity for H<SUB>1</SUB>-receptors in the guinea pig cerebral cortex in comparison to affinities for muscarinic and serotonin 5-HT<SUB>2</SUB>-receptors in the rat cerebral cortex, while the selectivity of PY-608 for the H<SUB>1</SUB>receptor was low. The inhibitory effects of these antiallergic agents on histamine-induced increase of vascular permeability in mice (ED<SUB>50</SUB>)were compared with the displacement of [<SUP>3</SUP>H]mepyramine binding to H<SUB>1</SUB>receptors in mouse brain ex vivo (ID<SUB>50</SUB>). 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 [<SUP>3</SUP>H]mepyramine binding to H<SUB>1</SUB>-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.


  • The Japanese Journal of Pharmacology

    The Japanese Journal of Pharmacology 73(4), 291-298, 1997-04-01

    The Japanese Pharmacological Society

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Cited by:  4


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