Volume 16 Supplement 1

Abstracts from the 7th International Conference on cGMP Generators, Effectors and Therapeutic Implications

Open Access

Identification and characterization of small molecular NPR-B receptor antagonists

  • Henriette Andresen1, 2,
  • Lise Román Moltzau1Email author,
  • Steffen Fagerheim1, 3,
  • David Gloriam4,
  • Trond Bach1, 3 and
  • Finn Olav Levy1, 3
BMC Pharmacology and Toxicology201516(Suppl 1):A70

https://doi.org/10.1186/2050-6511-16-S1-A70

Published: 2 September 2015

Background

Natriuretic peptides increase in heart failure. Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) activate the natriuretic peptide receptor (NPR)-A and C-type natriuretic peptide (CNP) the NPR-B, causing production of cyclic 3’,5’-guanosine monophosphate (cGMP). Our group has previously shown that CNP potentiates β1-adrenoceptor-mediated inotropic response by increasing cAMP levels. This is explained by a crosstalk between cGMP and cAMP, where cGMP produced by NPR-B inhibits phosphodiesterase (PDE) 3 from degrading cAMP. Increased β1-adrenoceptor signalling is harmful in heart failure which is the basis for use of β-blockers in heart failure therapy. Further, PDE3 inhibition has been associated with increased mortality in heart failure. Thus, an NPR-B antagonist could eliminate the unwanted effects due to PDE3 inhibition and increased β1-adrenoceptor signalling by CNP. There are no selective NPR-B antagonists available, and our aim is to identify and characterize novel non-peptide small molecular selective NPR-B antagonists for potential use in heart failure therapy.

Methods

Small molecular compounds were screened for activity and selectivity towards NPR-A and NPR-B, using a cGMP assay based on AlphaScreen technology. Based on this technology, we can identify compounds that interfere with BNP- and CNP-stimulated cGMP production through the NPR-A and NPR-B receptor, respectively. Antagonism properties can also be characterized.

Results and Conclusion

Potential NPR-B antagonists were identified by high throughput screening of about 20,000 compounds. Hits were tested against the NPR-A to determine selectivity, and characterized as non-competitive and reversible inhibitors of NPR-B response in HEK293 cells, displaying properties of negative allosteric modulators [1]. Information on structure and activity relationship (SAR), was collected and over 50 new compounds, clustered in five different groups of chemically related compounds, were designed in silicoand were tested for activity and selectivity towards NPR-A and NPR-B. From this testing, three out of five groups were found interesting. The ligands with the best antagonistic property from each of the 3 groups were used to select 60 more compounds by in silicodesign for further testing.

Authors’ Affiliations

(1)
Department of Pharmacology, University of Oslo and Oslo University Hospital
(2)
School of Pharmacy, University of Oslo
(3)
K.G. Jebsen Cardiac Research Centre and Center for Heart Failure Research, University of Oslo
(4)
Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen

References

  1. Bach T, Bergholtz S, Riise J, Qvigstad E, Skomedal T, Osnes JB, et al: Identification of small molecule NPR-B antagonists by high throughput screening - potential use in heart failure. Naunyn Schmiedebergs Arch Pharmacol. 2014, 387 (1): 5-14. 10.1007/s00210-013-0940-6.View ArticlePubMedGoogle Scholar

Copyright

© Andresen et al. 2015

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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