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rdf:type |
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lifeskim:mentions |
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pubmed:issue |
1-3
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pubmed:dateCreated |
2008-5-23
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pubmed:abstractText |
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.
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pubmed:language |
eng
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pubmed:journal |
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pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/4-iodo-2,5-dimethoxyphenylisopropyla...,
http://linkedlifedata.com/resource/pubmed/chemical/Amphetamines,
http://linkedlifedata.com/resource/pubmed/chemical/DNA,
http://linkedlifedata.com/resource/pubmed/chemical/Fibrinolytic Agents,
http://linkedlifedata.com/resource/pubmed/chemical/Inositol Phosphates,
http://linkedlifedata.com/resource/pubmed/chemical/Phenylurea Compounds,
http://linkedlifedata.com/resource/pubmed/chemical/Receptor, Serotonin, 5-HT2A,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Proteins,
http://linkedlifedata.com/resource/pubmed/chemical/Serotonin,
http://linkedlifedata.com/resource/pubmed/chemical/Serotonin Antagonists
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pubmed:status |
MEDLINE
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pubmed:month |
May
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pubmed:issn |
0014-2999
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pubmed:author |
pubmed-author:AdamsJohn WJW,
pubmed-author:Al-ShammaHussienH,
pubmed-author:BehanDominic PDP,
pubmed-author:ConnollyDaniel TDT,
pubmed-author:DosaPeterP,
pubmed-author:MorganMichaelM,
pubmed-author:OrtunoDannyD,
pubmed-author:RamirezJuanJ,
pubmed-author:RichmanJeremy GJG,
pubmed-author:ShiYunqingY,
pubmed-author:TeegardenBradley RBR,
pubmed-author:ThomsenWilliamW
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pubmed:issnType |
Print
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pubmed:day |
31
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pubmed:volume |
586
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
234-43
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pubmed:meshHeading |
pubmed-meshheading:18358471-Amphetamines,
pubmed-meshheading:18358471-Animals,
pubmed-meshheading:18358471-Aorta, Thoracic,
pubmed-meshheading:18358471-Bleeding Time,
pubmed-meshheading:18358471-Blood Platelets,
pubmed-meshheading:18358471-Blood Vessels,
pubmed-meshheading:18358471-Cell Membrane,
pubmed-meshheading:18358471-DNA,
pubmed-meshheading:18358471-Fibrinolytic Agents,
pubmed-meshheading:18358471-Humans,
pubmed-meshheading:18358471-Inositol Phosphates,
pubmed-meshheading:18358471-Male,
pubmed-meshheading:18358471-Muscle, Smooth, Vascular,
pubmed-meshheading:18358471-Phenylurea Compounds,
pubmed-meshheading:18358471-Platelet Aggregation,
pubmed-meshheading:18358471-Protein Binding,
pubmed-meshheading:18358471-Rats,
pubmed-meshheading:18358471-Rats, Sprague-Dawley,
pubmed-meshheading:18358471-Receptor, Serotonin, 5-HT2A,
pubmed-meshheading:18358471-Recombinant Proteins,
pubmed-meshheading:18358471-Serotonin,
pubmed-meshheading:18358471-Serotonin Antagonists,
pubmed-meshheading:18358471-Vasoconstriction
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pubmed:year |
2008
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pubmed:articleTitle |
Anti-thrombotic and vascular effects of AR246686, a novel 5-HT2A receptor antagonist.
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pubmed:affiliation |
Arena Pharmaceuticals, Inc. San Diego, CA 92121 USA. jadams@arenapharm.com
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pubmed:publicationType |
Journal Article
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