Pharmacology of SB-273779, a Nonpeptide Calcitonin Gene-Related Peptide 1 Receptor Antagonist
Calcitonin gene-related peptide (CGRP), a potent vasodilatory and cardiotonic peptide, has a potential role for CGRP in diverse physiologic and pathophysiologic situations such as congestive heart failure, diabetes, migraine, and neurogenic inflammation. Although a peptide CGRP receptor antagonist,...
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Published in | The Journal of pharmacology and experimental therapeutics Vol. 296; no. 3; pp. 768 - 775 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
United States
American Society for Pharmacology and Experimental Therapeutics
01.03.2001
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Subjects | |
Online Access | Get full text |
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Summary: | Calcitonin gene-related peptide (CGRP), a potent vasodilatory and cardiotonic peptide, has a potential role for CGRP in diverse
physiologic and pathophysiologic situations such as congestive heart failure, diabetes, migraine, and neurogenic inflammation.
Although a peptide CGRP receptor antagonist, CGRP 8-37, is available, its utility presents significant limitations for these indications. Here, we describe the properties of SB-(+)-273779
[ N -methyl- N -(2-methylphenyl)-3-nitro-4-(2-thiazolylsulfinyl)nitrobenzanilide], a selective nonpeptide antagonist of CGRP 1 receptor. SB-(+)-273779 inhibited 125 I-labeled CGRP binding to SK-N-MC (human neuroblastoma cells) and human cloned CGRP 1 receptor with K i values of 310 ± 40 and 250 ±15 nM, respectively. SB-(+)-273779 also inhibited CGRP (3 nM)-activated adenylyl cyclase in these
systems with IC 50 values of 390 ±10 nM (in SK-N-MC) and 210 ±16 nM (recombinant human CGRP receptors). Prolonged treatment (>30 min) of SK-N-MC
cells with SB-(+)-273779 followed by extensive washing resulted in reduction in maximum CGRP-mediated adenylyl cyclase activity,
suggesting that this compound has irreversible binding characteristics. In addition, SB-(+)-273779 antagonized CGRP-mediated
1) stimulation of intracellular Ca 2+ in recombinant CGRP receptors in HEK-293 cells, 2) inhibition of insulin-stimulated [ 14 C]deoxyglucose uptake in L6 cells, 3) vasodilation in rat pulmonary artery, and 4) decrease in blood pressure in anesthetized
rats. SB-(+)-273779 tested at 3 μM had no significant affinity for calcitonin, endothelin, angiotensin II, and α-adrenergic
receptors under standard ligand binding assays. SB-(+)-273779 also did not inhibit forskolin and pituitary adenylate cyclase-activating
polypeptide. These results suggest that SB-(+)-273779 is a valuable tool for studying CGRP-mediated functional responses in
complex biological systems. |
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Bibliography: | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0022-3565 1521-0103 |