Identification of small molecule NPR-B antagonists by high throughput screening--potential use in heart failure

Naunyn Schmiedebergs Arch Pharmacol. 2014 Jan;387(1):5-14. doi: 10.1007/s00210-013-0940-6. Epub 2013 Dec 3.


We found previously that stimulation of natriuretic peptide receptor (NPR)-B by C-type natriuretic peptide (CNP) in failing rat ventricle potentiates β1-adrenoceptor (β1-AR)-mediated inotropic response to noradrenaline through cGMP-mediated inhibition of phosphodiesterase (PDE) 3, thereby enhancing cAMP-mediated signalling. Increased cAMP-mediated signalling is deleterious in chronic heart failure (HF; basis for the use of β-blockers in HF) and we propose to consider NPR-B antagonists as new HF treatment in addition to conventional therapy. Since there is no NPR-B-selective antagonist available for clinical studies, we aimed at identifying a novel small molecule (non-peptide) NPR-B antagonist. An assay was developed and high throughput screening performed on a chemical library of about 20,000 small molecule compounds (<500 Da) to identify NPR-B antagonists based on inhibition of CNP-stimulated cGMP production in NPR-B-expressing HEK293 cells. The screen revealed several potential NPR-B antagonists, of which six were selected for further studies. Three showed selective NPR-B vs NPR-A inhibition and three were partially selective. The compounds mediated reversible, noncompetitive inhibition and most likely act as allosteric modulators binding outside the agonist binding site of NPR-B. In rat ventricular muscle strips, the potentiating effect of CNP upon β1-AR-evoked inotropic effects could be attenuated by at least one of these compounds. We identified several small molecule NPR-B antagonists by high throughput screening and show in a functional heart preparation that blocking NPR-B stimulation with a small molecule compound can reduce the potentiating effect of CNP on the β1-AR-mediated inotropic response to noradrenaline.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Drug Evaluation, Preclinical / methods
  • HEK293 Cells
  • Heart Failure / diagnosis*
  • Heart Failure / drug therapy*
  • Heart Failure / genetics
  • Heart Ventricles / drug effects
  • High-Throughput Screening Assays / methods
  • High-Throughput Screening Assays / statistics & numerical data*
  • Humans
  • Molecular Sequence Data
  • Organ Culture Techniques
  • Rats
  • Receptors, Atrial Natriuretic Factor / antagonists & inhibitors*
  • Receptors, Atrial Natriuretic Factor / genetics
  • Receptors, Atrial Natriuretic Factor / metabolism


  • Receptors, Atrial Natriuretic Factor
  • atrial natriuretic factor receptor B