Document Detail

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.
MedLine Citation:
PMID:  9165365     Owner:  NLM     Status:  MEDLINE    
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.
M Kakiuchi; T Ohashi; K Musoh; K Kawamura; K Morikawa; H Kato
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Publication Detail:
Type:  Comparative Study; In Vitro; Journal Article    
Journal Detail:
Title:  Japanese journal of pharmacology     Volume:  73     ISSN:  0021-5198     ISO Abbreviation:  Jpn. J. Pharmacol.     Publication Date:  1997 Apr 
Date Detail:
Created Date:  1997-08-27     Completed Date:  1997-08-27     Revised Date:  2006-11-15    
Medline Journal Info:
Nlm Unique ID:  2983305R     Medline TA:  Jpn J Pharmacol     Country:  JAPAN    
Other Details:
Languages:  eng     Pagination:  291-8     Citation Subset:  IM    
Research and Development Division, Hokuriku Seiyaku Co., Ltd., Fukui, Japan.
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MeSH Terms
Administration, Oral
Anti-Allergic Agents / metabolism*,  pharmacology
Benzoxepins / administration & dosage,  chemistry,  pharmacokinetics,  pharmacology*
Binding, Competitive
Capillary Permeability / drug effects
Cerebral Cortex / drug effects,  metabolism*
Dose-Response Relationship, Drug
Guinea Pigs
Histamine / toxicity
Histamine H1 Antagonists / administration & dosage,  chemistry,  pharmacokinetics,  pharmacology*
Isotope Labeling
Lethal Dose 50
Lung / drug effects,  metabolism
Mice, Inbred ICR
Pyridines / administration & dosage,  chemistry,  pharmacokinetics,  pharmacology*
Pyrilamine / metabolism
Receptors, Histamine H1 / drug effects*,  metabolism
Receptors, Muscarinic / drug effects,  metabolism
Receptors, Serotonin / drug effects,  metabolism
Reference Standards
Structure-Activity Relationship
Reg. No./Substance:
0/Anti-Allergic Agents; 0/Benzoxepins; 0/HSR 609; 0/Histamine H1 Antagonists; 0/PY 608; 0/Pyridines; 0/Receptors, Histamine H1; 0/Receptors, Muscarinic; 0/Receptors, Serotonin; 51-45-6/Histamine; 91-84-9/Pyrilamine

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