Anti-thrombotic and vascular effects of AR246686, a novel 5-HT2A receptor antagonist
Autor: | Peter I. Dosa, Yunqing Shi, Bradley Teegarden, Hussien A. Al-Shamma, Dominic P. Behan, John W. Adams, Michael Morgan, Jeremy G. Richman, William Thomsen, Daniel T. Connolly, Juan Ramirez, Danny Ortuno |
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Rok vydání: | 2008 |
Předmět: |
Blood Platelets
Male Serotonin medicine.medical_specialty Bleeding Time Vascular smooth muscle Platelet Aggregation medicine.drug_class Inositol Phosphates Aorta Thoracic Muscle Smooth Vascular Rats Sprague-Dawley Fibrinolytic Agents Bleeding time Internal medicine medicine Animals Humans Potency Receptor Serotonin 5-HT2A Platelet Inositol phosphate Receptor Pharmacology chemistry.chemical_classification medicine.diagnostic_test business.industry Phenylurea Compounds Amphetamines Cell Membrane Antagonist DNA Receptor antagonist Recombinant Proteins Rats Endocrinology chemistry Vasoconstriction Blood Vessels Serotonin Antagonists business Protein Binding |
Zdroj: | European Journal of Pharmacology. 586:234-243 |
ISSN: | 0014-2999 |
Popis: | We have evaluated the anti-platelet and vascular pharmacology of AR246686, a novel 5-hydroxytryptamine2A (5-HT2A) receptor antagonist. AR246686 displayed high affinity binding to membranes of HEK cells stably expressing recombinant human and rat 5-HT2A receptors (Ki=0.2 nM and 0.4 nM, respectively). Functional antagonism (IC50=1.9 nM) with AR246686 was determined by inhibition of ligand-independent inositol phosphate accumulation in the 5-HT2A stable cell line. We observed 8.7-fold and 1360-fold higher affinity of AR246686 for the 5-HT2A receptor vs. 5-HT2C and 5-HT2B receptors, respectively. AR246686 inhibited 5-HT-induced amplification of ADP-stimulated human platelet aggregation (IC50=21 nM). Similar potency was observed for inhibition of 5-HT stimulated DNA synthesis in rat aortic smooth muscle cells (IC(50)=10 nM) and 5-HT-mediated contraction in rat aortic rings. Effects of AR246686 on arterial thrombosis and bleeding time were studied in a rat model of femoral artery occlusion. Oral dosing of AR246686 to rats resulted in prolongation of time to occlusion at 1 mg/kg, whereas increased bleeding time was observed at a dose of 20 mg/kg. In contrast, both bleeding time and time to occlusion were increased at the same dose (10 mg/kg) of clopidogrel. These results demonstrate that AR246686 is a high affinity 5-HT2A receptor antagonist with potent activity on platelets and vascular smooth muscle. Further, oral administration results in anti-thrombotic effects at doses that are free of significant effects on traumatic bleeding time. |
Databáze: | OpenAIRE |
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