title: 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.
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 nonamphoteric basic compound PY-608 (8-fluoro-5,11-dihydro-11-(1-methyl-4-piperidylidene)benz[b]oxe pino- [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.
authors.affiliation: Research and Development Division, Hokuriku Seiyaku Co., Ltd., Fukui, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Kakiuchi
authors.forename: T
authors.initials: T
authors.lastname: Ohashi
authors.forename: K
authors.initials: K
authors.lastname: Musoh
authors.forename: K
authors.initials: K
authors.lastname: Kawamura
authors.forename: K
authors.initials: K
authors.lastname: Morikawa
authors.forename: H
authors.initials: H
authors.lastname: Kato
mesh_terms: D000284:Administration, Oral; D000818:Animals; D018926:Anti-Allergic Agents / Q000378:metabolism* / Q000494:pharmacology; D001584:Benzoxepins / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D001667:Binding, Competitive; D002199:Capillary Permeability / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006632:Histamine / Q000633:toxicity; D006634:Histamine H1 Antagonists / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D066298:In Vitro Techniques; D007553:Isotope Labeling; D007928:Lethal Dose 50; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011725:Pyridines / Q000008:administration & dosage / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011738:Pyrilamine / Q000378:metabolism; D051381:Rats; D011969:Receptors, Histamine H1 / Q000187:drug effects* / Q000378:metabolism; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects / Q000378:metabolism; D012015:Reference Standards; D013329:Structure-Activity Relationship
chemical_list: D018926:Anti-Allergic Agents; D001584:Benzoxepins; C104838:HSR 609; D006634:Histamine H1 Antagonists; C107369:PY 608; D011725:Pyridines; D011969:Receptors, Histamine H1; D011976:Receptors, Muscarinic; D011985:Receptors, Serotonin; D006632:Histamine; D011738:Pyrilamine