Journal
COMMUNICATIONS BIOLOGY
Volume 5, Issue 1, Pages -Publisher
NATURE PORTFOLIO
DOI: 10.1038/s42003-022-04143-9
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Funding
- National Institute of Mental Health's Psychoactive Drug Screening Program [HHSN-271-2018-00023-C]
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) at the NIH [R01AR070093]
- National Center for Advancing Translational Sciences Intramural Research Program
- NIH from NIGMS [P20 GM125503]
- University Graduate School at Florida International University
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Specific small molecule RXFP2 agonists induce proper development of reproduction and bone through experimental validation, providing potential for oral administration.
Specific small molecule RXFP2 agonists with favorable pharmacokinetic properties induce gubernacular invagination in mouse embryos, increase mineralization activity in human osteoblasts in vitro, and improve bone trabecular parameters in adult mice. The relaxin/insulin-like family peptide receptor 2 (RXFP2) belongs to the family of class A G-protein coupled receptors (GPCRs) and it is the only known target for the insulin-like factor 3 peptide (INSL3). The importance of this ligand-receptor pair in the development of the gubernacular ligament during the transabdominal phase of testicular descent is well established. More recently, RXFP2 has been implicated in maintaining healthy bone formation. In this report, we describe the discovery of a small molecule series of RXFP2 agonists. These compounds are highly potent, efficacious, and selective RXFP2 allosteric agonists that induce gubernacular invagination in mouse embryos, increase mineralization activity in human osteoblasts in vitro, and improve bone trabecular parameters in adult mice. The described RXFP2 agonists are orally bioavailable and display favorable pharmacokinetic properties, which allow for future evaluation of the therapeutic benefits of modulating RXFP2 activation in disease models.
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