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Submitted on September 19, 2003
Accepted on April 12, 2004
Cell and Cancer Biology Branch and Vascular Biology Faculty, National Cancer Institute, National Institutes of Health (A.M., T.W.M., F.C.), Bethesda, MD 20892; Department of Chemical Sciences, S. Pablo-CEU University (M.J.), 28668 Madrid, Spain; Section of Pharmacology, National Institute of Mental Health, National Institutes of Health (C.B.), Bethesda, MD 20892; and Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health (L.N.), Bethesda, MD 20892
* To whom correspondence should be addressed. E-mail: martinea{at}mail.nih.gov.
Adrenomedullin (AM) is a peptide hormone implicated in blood pressure regulation and in the pathophysiology of important diseases such as hypertension, cancer, and diabetes. However, non-peptidic modulators of this peptide, that could be used to clinically regulate its actions, are not available. We present here an efficient new method to screen a large library of small molecules. This technology was applied to the identification of positive and negative modulators of AM function. A two-tier screening strategy was developed in which the first screening entails disruption of the interaction between the peptide and a neutralizing monoclonal antibody. Selected compounds were further characterized by their ability to modulate second messengers in cells containing specific AM receptors. A parallel screen against gastrin releasing peptide (GRP) selected a different subset of molecules, confirming the specificity of the screening method. Identified AM positive regulators reduced blood pressure in vivo whereas AM negative regulators mediated vasoconstriction, as predicted by the vasodilatory activity of AM. Binding of the small molecules to immobilized AM was demonstrated by surface plasmon resonance assays with KDs ranging from 7.76 x 10 -9 to 4.14 x 10 -6 M. Preclinical development of AM modulators may result in useful drugs for the prevention and treatment of hypertension, cancer, and diabetes.
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