Identification of vasoactive nonpeptidic positive and negative modulators of adrenomedullin using a neutralizing antibody-based screening strategy.

MARTÍNEZ A, JULIÁN M, BREGONZIO C, NOTARI L, MOODY TW, CUTTITTA F

ENDOCRINOLOGY

Año: 2004 vol. 145 p. 3858 - 3858

0013-7227

p class="abstract">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, nonpeptidic 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 selected a different subset of molecules, confirming the specificity of the screening method. Identified AM-positive regulators reduced b