Identification of small-molecule agonists of human relaxin family receptor 1 (RXFP1) by using a homogenous cell-based cAMP assay
Open accessAbstract
The relaxin hormone is involved in a variety of biological functions, including female reproduction and parturition, as well as regulation of cardiovascular, renal, pulmonary, and hepatic functions. It regulates extracellular matrix remodeling, cell invasiveness, proliferation, differentiation, and overall tissue homeostasis. The G protein-coupled receptor (GPCR) relaxin family receptor 1 (RXFP1) is a cognate relaxin receptor that mainly signals through cyclic AMP second messenger. Although agonists of the receptor could have a wide range of pharmacologic utility, until now there have been no reported small-molecule agonists for relaxin receptors. Here, we report the development of a quantitative high-throughput platform for an RXFP1 agonist screen based on homogenous cell-based HTRF cyclic AMP (cAMP) assay technology. Two small molecules of similar structure were independently identified from a screen of more than 365 677 compounds. Neither compound showed activity in a counterscreen with HEK293T cells transfected with an unrelated GPCR vasopressin 1b receptor. These small-molecule agonists also demonstrated selectivity against the RXFP2 receptor, providing a basis for future medicinal chemistry optimization of selective relaxin receptor agonists.
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A NIH team identified two lead hits following screening of 367,000 compounds, including a lead ML290, from which a derivative AZD5462 was obtained.
“a NIH team identified two lead hits following meticulous screening of 367,000 compounds, 9 including a lead ML290, from which a derivative AZD5462 was obtained (Figure ). 10”
From Revivifying research on relaxin receptor-targeted therapy for cardiovascular diseases (2025) · cites this paper as [9]
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- Authors
- Chen, C. Z., Southall, N., Xiao, J., Marugan, J. J., Ferrer, M., Hu, X., Jones, R. E., Feng, S., Agoulnik, I. U., Zheng, W., & Agoulnik, A. I.
- Affiliations
- National Institutes of Health (US)
- Baylor College of Medicine (US)
- Florida International University (US)
- Corresponding author
- Zheng, Wei
- Agoulnik, Alexander I.
- ORCID
- Venue
- SLAS Discovery
- Publisher
- Elsevier BV
- Published
- 2013-07
- Volume
- 18
- Issue
- 6
- Pages
- 670-677
- ISSN
- 2472-5552 (ISSN-L)
- PMC
- PMC4804196
- OpenAlex
- W2111428148
- Cited by
- 31
- References
- 19
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 1 · 2023: 1 · 2021: 2 · 2020: 1 · 2019: 3 · 2018: 3 · 2017: 2 · 2016: 5 · 2015: 4 · 2014: 2 · 2013: 2
- FWCI
- 2.47
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- SLAS DISCOVERY (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- University of Illinois at Urbana-Champaign
- National Institute of Mental Health (U54 MH084681, R03MH085705)
- National Human Genome Research Institute (Z01HG200319)
- Topics
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Pregnancy-related medical research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Receptor Mechanisms and Signaling
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- RXFP1, small molecule agonists, G protein-coupled receptors, cAMP signaling, homogeneous time-resolved fluorescence, high-throughput screening, receptor selectivity
- MeSH terms
- Cyclic AMP, Cell Line, Humans, Receptors, Peptide, Receptors, G-Protein-Coupled, Small Molecule Libraries, High-Throughput Screening Assays, HEK293 Cells
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