APD791, 3-Methoxy-N-(3-(1-methyl-1H-pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide, a Novel 5-Hydroxytryptamine 2A Receptor Antagonist: Pharmacological Profile, Pharmacokinetics, Platelet Activity and Vascular Biology
We have evaluated the receptor pharmacology, antiplatelet activity, and vascular pharmacology of APD791 [3-methoxy- N -(3-(1-methyl-1 H -pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide] a novel 5-hydroxytryptamine 2A (5-HT 2A ) receptor antagonist. APD791 displayed high-affinity binding to memb...
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 331; no. 1; pp. 96 - 103 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.10.2009
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Subjects | |
Online Access | Get full text |
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Summary: | We have evaluated the receptor pharmacology, antiplatelet activity, and vascular pharmacology of APD791 [3-methoxy- N -(3-(1-methyl-1 H -pyrazol-5-yl)-4-(2-morpholinoethoxy)phenyl)benzamide] a novel 5-hydroxytryptamine 2A (5-HT 2A ) receptor antagonist. APD791 displayed high-affinity binding to membranes ( K i = 4.9 nM) and functional inverse agonism of inositol phosphate accumulation (IC 50 = 5.2 nM) in human embryonic kidney cells stably expressing the human 5-HT 2A receptor. In competition binding assays, APD791 was greater than 2000-fold selective for the 5-HT 2A receptor versus 5-HT 2C and 5-HT 2B receptors, and was inactive when tested against a wide panel of other G-protein-coupled receptors. APD791 inhibited 5-HT-mediated
amplification of ADP-stimulated human and dog platelet aggregation (IC 50 = 8.7 and 23.1 nM, respectively). Similar potency was observed for inhibition of 5-HT-stimulated DNA synthesis in rabbit
aortic smooth muscle cells (IC 50 = 13 nM) and 5-HT-mediated vasoconstriction in rabbit aortic rings. Oral administration of APD791 to dogs resulted in acute
(1-h) and subchronic (10-day) inhibition of 5-HT-mediated amplification of collagen-stimulated platelet aggregation in whole
blood. Two active metabolites, APD791-M1 and APD791-M2, were generated upon incubation of APD791 with human liver microsomes
and were also indentified in dogs after oral administration of APD791. The affinity and selectivity profiles of both metabolites
were similar to APD791. These results demonstrate that APD791 is an orally available, high-affinity 5-HT 2A receptor antagonist with potent activity on platelets and vascular smooth muscle. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.109.153189 |