AT-1015, a Novel Serotonin (5-HT)2 Receptor Antagonist, Blocks Vascular and Platelet 5-HT2A Receptors and Prevents the Laurate-Induced Peripheral Vascular Lesion in Rats
| Autor: | Hiroshi Yamamoto, Tsukao Nishimori, Ayahito Kimura, Hideaki Kihara, Ken Hirose, Noriko Sasaki, Ryota Yoshimoto, Hajime Koganei, Masataka Shoji |
|---|---|
| Rok vydání: | 2000 |
| Předmět: |
Blood Platelets
Male medicine.medical_specialty Ketanserin Platelet Aggregation medicine.drug_class Sarpogrelate chemistry.chemical_compound Isonipecotic Acids Internal medicine medicine Animals Humans Receptor Serotonin 5-HT2A Rats Wistar Receptor Aorta 5-HT receptor Peripheral Vascular Diseases Pharmacology business.industry Antagonist Receptor antagonist Rats Cilostazol Disease Models Animal Endocrinology chemistry Vasoconstriction Receptors Serotonin Serotonin Antagonists medicine.symptom Cardiology and Cardiovascular Medicine business Laurates medicine.drug |
| Zdroj: | Journal of Cardiovascular Pharmacology. 35:523-530 |
| ISSN: | 0160-2446 |
| DOI: | 10.1097/00005344-200004000-00002 |
| Popis: | The serotonin (5-HT2A) antagonistic activities and the protective effect on laurate-induced peripheral vascular lesions of AT-1015, a novel 5-HT2 receptor antagonist, were investigated. In platelet aggregation, AT-1015 selectively inhibited in vitro 5-HT2A receptor-mediated aggregation, and the activity was almost equivalent to that of ketanserin (5-HT2A/2C receptor antagonist) and 100 times more potent than sarpogrelate (5-HT2A receptor antagonist). AT-1015 also inhibited 5-HT2A receptor-mediated aggregation by oral administration in rat, and the dose required for inhibition was equivalent to ketanserin. In a 5-HT-induced vasoconstriction study in rat, AT-1015 slightly reduced maximal contraction and caused a rightward shift of the concentration-response curve (pKB value, 9.5), which was unlike competitive inhibitors such as ketanserin and sarpogrelate (pA2 value, 9.3 and 8.7, respectively). Moreover, the ex vivo inhibitory activity significantly remained after oral administration (1 mg/kg). In the rat peripheral vascular lesion model, AT-1015 (1 mg/kg, p.o.) effectively prevented progression of peripheral lesions, and it was more potent compared with ketanserin, sarpogrelate, and cilostazol. These results suggest that AT-1015 is a potent 5-HT2A receptor antagonist, and its insurmountable antagonism may be relevant to its therapeutic potential in peripheral vascular disease. |
| Databáze: | OpenAIRE |
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