Anti-thrombotic and vascular effects of AR246686, a novel 5-HT2A receptor antagonist.
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.
Adams
John W
JW
Arena Pharmaceuticals, Inc. San Diego, CA 92121 USA. jadams@arenapharm.com
Ramirez
Juan
J
Ortuno
Danny
D
Shi
Yunqing
Y
Thomsen
William
W
Richman
Jeremy G
JG
Morgan
Michael
M
Dosa
Peter
P
Teegarden
Bradley R
BR
Al-Shamma
Hussien
H
Behan
Dominic P
DP
Connolly
Daniel T
DT
D000662:Amphetamines / Q000378:metabolism; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001760:Bleeding Time; D001792:Blood Platelets / Q000187:drug effects; D001808:Blood Vessels / Q000187:drug effects*; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D004247:DNA / Q000096:biosynthesis / Q000235:genetics; D005343:Fibrinolytic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D006801:Humans; D007295:Inositol Phosphates / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010671:Phenylurea Compounds / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D017207:Rats, Sprague-Dawley; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects*; D011994:Recombinant Proteins / Q000737:chemistry; D012701:Serotonin / Q000378:metabolism; D012702:Serotonin Antagonists / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects
C531034:AR 246686; D000662:Amphetamines; D005343:Fibrinolytic Agents; D007295:Inositol Phosphates; D010671:Phenylurea Compounds; D044402:Receptor, Serotonin, 5-HT2A; D011994:Recombinant Proteins; D012702:Serotonin Antagonists; D012701:Serotonin; D004247:DNA; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine