Synthesis and Pharmacology of 3,4-Dihydro-3-oxo-1,4-benzoxazine-8-carboxamide Derivatives, a New Class of Potent Serotonin-3 (5-HT3) Receptor Antagonists
| Autor: | Takanobu Kuroita, Mitsuharu Sano, Ken-ichi Inaba, Mitsuyoshi Yasumoto, Takemi Fukuda, Tetsuya Tahara, Takeshi Kawakita |
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| Rok vydání: | 1992 |
| Předmět: |
Male
Magnetic Resonance Spectroscopy Stereochemistry medicine.drug_class Carboxamide 5-HT3 receptor Bridged Bicyclo Compounds Structure-Activity Relationship Oxazines Drug Discovery medicine Animals Moiety Receptor Cyclophosphamide ED50 biology Chemistry Rats Inbred Strains General Chemistry General Medicine Bridged Bicyclo Compounds Heterocyclic Rats Quipazine Doxorubicin Spiperone biology.protein Antiemetics Serotonin Antagonists Serotonin Cisplatin |
| Zdroj: | Chemical and Pharmaceutical Bulletin. 40:624-630 |
| ISSN: | 1347-5223 0009-2363 |
| Popis: | A series of 3,4-dihydro-3-oxo-1,4-benzoxazine-8-carboxamide derivatives was synthesized and evaluated for serotonin-3 (5-HT3) receptor antagonistic activity assessed by their ability to antagonize the von Bezold-Jarish (BJ) effect in rats. Derivatives bearing 1-azabicyclo[2.2.2]oct-3-yl moiety as a basic function attached to the carboxamide at position 8 showed more potent antagonistic activity than those bearing the other three basic moieties. Structure-activity relationships of this series showed that methyl and chloro groups were more effective as substituents at positions 4 and 6, respectively. The representative compound 15 (Y-25130) in this series showed potent antagonistic activity on the BJ effect (ED50 = 1.3 micrograms/kg i.v.), high affinity for 5-HT3 receptor (Ki = 2.9 nM) and complete protection against cisplatin-induced emesis in dogs at a dose of 0.1 mg/kg i.v. |
| Databáze: | OpenAIRE |
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