Targeting the relaxin-3/RXFP3 system: a patent review for the last two decades

References

• Samuel CS, Parry LJ, Summers RJ. Physiological or pathological-a role for relaxin in the cardiovascular system? Curr Opin Pharmacol. 2003;3(2):152–158. doi: 10.1016/S1471-4892(03)00011-0
   PubMed Web of Science ®Google Scholar
• Sherwood OD. Relaxin’s physiological roles and other diverse actions. Endocr Rev. 2004;25(2):205–234. doi: 10.1210/er.2003-0013
   PubMed Web of Science ®Google Scholar
• Gundlach AL, Ma S, Sang Q, et al. Relaxin family peptides and receptors in mammalian brain. Ann N Y Acad Sci. 2009;160(1):226–235. doi: 10.1111/j.1749-6632.2009.03956.x
   Google Scholar
• Callander GE, Bathgate RA. Relaxin family peptide systems and the central nervous system. Cell Mol Life Sci. 2010;67(14):2327–2341. doi: 10.1007/s00018-010-0304-z
   PubMed Web of Science ®Google Scholar
• Gundlach AL, Smith CM, Ryan PJ, et al. Relaxins. In: Kastin AJ, editor. Handbook of biologically active peptides. Academic Press; 2013. p. 907–916. doi: 10.1016/B978-0-12-385095-9.00121-4
   Google Scholar
• Bathgate RA, Halls ML, van der Westhuizen ET, et al. Relaxin family peptides and their receptors. Physiol Rev. 2013;93(1):405–480. doi: 10.1152/physrev.00001.2012
   PubMed Web of Science ®Google Scholar
• Kong RC, Shilling PJ, Lobb DK, et al. Membrane receptors: structure and function of the relaxin family peptide receptors. Mol Cell Endocrinol. 2010;320(1–2):1–15. doi: 10.1016/j.mce.2010.02.003
   PubMed Web of Science ®Google Scholar
• Ma S, Smith CM, Blasiak A, et al. Distribution, physiology and pharmacology of relaxin-3/RXFP3 systems in brain. Br J Pharmacol. 2017;174(10):1034–1048. doi: 10.1111/bph.13659
   PubMed Web of Science ®Google Scholar
• Hsu SY, Nakabayashi K, Nishi S, et al. Activation of orphan receptors by the hormone relaxin. Science. 2002;295(5555):671–674. doi: 10.1126/science.1065654
   PubMed Web of Science ®Google Scholar
• Kumagai J, Hsu SY, Matsumi H, et al. INSL3/Leydig insulin-like peptide activates the LGR8 receptor important in testis descent. J Biol Chem. 2002;277(35):31283–31286. doi: 10.1074/jbc.C200398200
   PubMed Web of Science ®Google Scholar
• Liu C, Chen J, Sutton S, et al. Identification of relaxin-3/INSL7 as a ligand for GPCR142. J Biol Chem. 2003;278(50):50765–50770. doi: 10.1074/jbc.M308996200
   PubMed Web of Science ®Google Scholar
• Liu C, Eriste E, Sutton S, et al. Identification of relaxin-3/INSL7 as an endogenous ligand for the orphan G-protein-coupled receptor GPCR135. J Biol Chem. 2003;278(50):50754–50764. doi: 10.1074/jbc.M308995200
   PubMed Web of Science ®Google Scholar
• Chen J, Kuei C, Sutton SW, et al. Pharmacological characterization of relaxin-3/INSL7 receptors GPCR135 and GPCR142 from different mammalian species. J Pharmacol Exp Ther. 2005;312(1):83–95. doi: 10.1124/jpet.104.073486
   PubMed Web of Science ®Google Scholar
• Sutton SW, Bonaventure P, Kuei C, et al. G-protein-coupled receptor (GPCR)-142 does not contribute to relaxin-3 binding in the mouse brain: further support that relaxin-3 is the physiological ligand for GPCR135. Neuroendocrinology. 2005;82(3–4):139–150. doi: 10.1159/000091267
   PubMed Web of Science ®Google Scholar
• Van der Westhuizen ET, Sexton PM, Bathgate RA, et al. Responses of GPCR135 to human gene 3 (H3) relaxin in CHO-K1 cells determined by microphysiometry. Ann N Y Acad Sci. 2005;1041(1):332–337. doi: 10.1196/annals.1282.053
   PubMedGoogle Scholar
• Tanaka M. Relaxin-3/insulin-like peptide 7, a neuropeptide involved in the stress response and food intake. FEBS J. 2010;277(24):4990–4997. doi: 10.1111/j.1742-4658.2010.07931.x
   PubMed Web of Science ®Google Scholar
• Kumar JR, Rajkumar R, Jayakody T, et al. Relaxin’ the brain: a case for targeting the nucleus incertus network and relaxin-3/RXFP3 system in neuropsychiatric disorders. Br J Pharmacol. 2017;174(10):1061–1076. doi: 10.1111/bph.13564
   PubMed Web of Science ®Google Scholar
• Tanaka M, Iijima N, Miyamoto Y, et al. Neurons expressing relaxin 3/INSL 7 in the nucleus incertus respond to stress. Eur J Neurosci. 2005;21(6):1659–1670. doi: 10.1111/j.1460-9568.2005.03980.x
   PubMed Web of Science ®Google Scholar
• Banerjee A, Shen PJ, Ma S, et al. Swim stress excitation of nucleus incertus and rapid induction of relaxin-3 expression via CRF1 activation. Neuropharmacology. 2010;58(1):145–155. doi: 10.1016/j.neuropharm.2009.06.019
   PubMed Web of Science ®Google Scholar
• Watanabe Y, Miyamoto Y, Matsuda T, et al. Relaxin-3/INSL7 regulates the stress-response system in the rat hypothalamus. J Mol Neurosci. 2011;43(2):169–174. doi: 10.1007/s12031-010-9468-0
   PubMed Web of Science ®Google Scholar
• McGowan BM, Minnion JS, Murphy KG, et al. Relaxin-3 stimulates the neuro-endocrine stress axis via corticotrophin-releasing hormone. J Endocrinol. 2014;221(2):337–346. doi: 10.1530/JOE-13-0603
   PubMed Web of Science ®Google Scholar
• Smith CM, Lawrence AJ, Sutton SW, et al. Behavioral phenotyping of mixed background (129S5: B6) relaxin-3 knockout mice. Ann N Y Acad Sci. 2009;1160(1):236–241. doi: 10.1111/j.1749-6632.2009.03953.x
   PubMedGoogle Scholar
• Nakazawa CM, Shikata K, Uesugi M, et al. Prediction of relaxin-3-induced downstream pathway resulting in anxiolytic-like behaviors in rats based on a microarray and peptidome analysis. J Recept Signal Transduction Res. 2013;33(4):224–233. doi: 10.3109/10799893.2012.756895
   PubMed Web of Science ®Google Scholar
• Ryan PJ, Buchler E, Shabanpoor F, et al. Central relaxin-3 receptor (RXFP3) activation decreases anxiety- and depressive-like behaviours in the rat. Behav Brain Res. 2013;244:142–151. doi: 10.1016/j.bbr.2013.01.034
   PubMed Web of Science ®Google Scholar
• McGowan BM, Stanley SA, Smith KL, et al. Central relaxin-3 administration causes hyperphagia in male Wistar rats. Endocrinology. 2005;146(8):3295–3300. doi: 10.1210/en.2004-1532
   PubMed Web of Science ®Google Scholar
• Sutton SW, Shelton J, Smith C, et al. Metabolic and neuroendocrine responses to RXFP3 modulation in the central nervous system. Ann N Y Acad Sci. 2009;1160(1):242–249. doi: 10.1111/j.1749-6632.2008.03812.x
   PubMedGoogle Scholar
• Ganella DE, Callander GE, Ma S, et al. Modulation of feeding by chronic rAAV expression of a relaxin-3 peptide agonist in rat hypothalamus. Gene Ther. 2013;20(7):703–716. doi: 10.1038/gt.2012.83
   PubMed Web of Science ®Google Scholar
• Calvez J, de Avila C, Matte LO, et al. Role of relaxin-3/RXFP3 system in stress-induced binge-like eating in female rats. Neuropharmacology. 2016;102:207–215. doi: 10.1016/j.neuropharm.2015.11.014
   PubMed Web of Science ®Google Scholar
• Calvez J, de Avila C, Timofeeva E. Sex-specific effects of relaxin-3 on food intake and body weight gain. Br J Pharmacol. 2017;174(10):1049–1060. doi: 10.1111/bph.13530
   PubMed Web of Science ®Google Scholar
• de Avila C, Chometton S, Lenglos C, et al. Differential effects of relaxin-3 and a selective relaxin-3 receptor agonist on food and water intake and hypothalamic neuronal activity in rats. Behav Brain Res. 2018;336:135–144. doi: 10.1016/j.bbr.2017.08.044
   PubMed Web of Science ®Google Scholar
• Ryan PJ, Krstew EV, Sarwar M, et al. Relaxin-3 mRNA levels in nucleus incertus correlate with alcohol and sucrose intake in rats. Drug Alcohol Depend. 2014;140:8–16. doi: 10.1016/j.drugalcdep.2014.04.017
   PubMed Web of Science ®Google Scholar
• Walker AW, Smith CM, Chua BE, et al. Relaxin-3 receptor (RXFP3) signalling mediates stress-related alcohol preference in mice. PLoS One. 2015;10(4):e0122504. doi: 10.1371/journal.pone.0122504
   PubMed Web of Science ®Google Scholar
• Ryan PJ, Kastman HE, Krstew EV, et al. Relaxin-3/RXFP3 system regulates alcohol-seeking. Proc Natl Acad Sci USA. 2013;110(51):20789–20794. doi: 10.1073/pnas.1317807110
   PubMed Web of Science ®Google Scholar
• Walker LC, Kastman HE, Krstew EV, et al. Central amygdala relaxin-3/relaxin family peptide receptor 3 signalling modulates alcohol seeking in rats. Br J Pharmacol. 2017;174(19):3359–3369. doi: 10.1111/bph.13955
   PubMed Web of Science ®Google Scholar
• Eisai R&D Management Co Ltd. Screening method, WO2005075641. 2005.
   Google Scholar
• Eisai R&D Management Co Ltd. Peptide having food intake stimulating effect and method for screening for the peptide, WO2006109855. 2006.
   Google Scholar
• Eisai R&D Management Co Ltd. Peptide having anti-anxiety effect and method for screening thereof, WO2006118131. 2006.
   Google Scholar
• Universitaetsklinikum Jena. Method for early diagnosis of carcinomas of the anogenital tract, EP2308998. 2011.
   Google Scholar
• Unknown Assignee. Use of rxfp1/3 inhibitor in preparation of medication for preventing or treating adolescent idiopathic scoliosis disease, WO2022147897. 2022.
   Google Scholar
• Howard Florey Institute of Experimental Physiology and Medicine. Human 3 relaxin, WO2003030930. 2003.
   Google Scholar
• Howard Florey Institute of Experimental Physiology and Medicine, the University of Melbourne. Relaxin superfamily peptide analogues, WO2004113381. 2004.
   Google Scholar
• Howard Florey Institute of Experimental Physiology and Medicine. Modified relaxin polypeptides, WO2012031327. 2012.
   Google Scholar
• Howard Florey Institute of Experimental Physiology and Medicine. Modified relaxin polypeptides, US20140024592. 2014.
   Google Scholar
• Howard Florey Institute of Experimental Physiology and Medicine. Treatments for substance abuse and addiction, WO2012031328. 2012.
   Google Scholar
• Howard Florey Institute of Experimental Physiology and Medicine, the University of Queensland. Single chain relaxin polypeptides, WO2012031326. 2012.
   Google Scholar
• University of Queensland, Howard Florey Institute of Experimental Physiology and Medicine. Single chain relaxin polypeptides, US20140038895. 2014.
   Google Scholar
• University of Queensland, Howard Florey Institute of Experimental Physiology and Medicine. Single chain relaxin polypeptides, US9359422. 2016.
   Google Scholar
• University of Queensland, Howard Florey Institute of Experimental Physiology and Medicine. Single chain relaxin polypeptides, EP2614075. 2016.
   Google Scholar
• Janssen Pharmaceutica NV. Relaxin3-GPCR135 complexes and their production and use, WO2004082598. 2004.
   Google Scholar
• Janssen Pharmaceutica NV. Relaxin3-GPCR135 complexes and their production and use, US20050074814. 2005.
   Google Scholar
• Janssen Pharmaceutica NV. Relaxin3-GPCR135 complexes and their production and use, US20060188956. 2006.
   Google Scholar
• Janssen Pharmaceutica NV. Complexes of GPCR142 and relaxin3 or INSL5, and their production and use, WO2005014616. 2005.
   Google Scholar
• Janssen Pharmaceutica NV. Complexes of GPCR142 and relaxin3 or INSL5, and their production and use, US20050059089. 2005.
   Google Scholar
• Janssen Pharmaceutica NV. Relaxin-chimeric polypeptides and their preparation and use, WO2006026355. 2006.
   Google Scholar
• Imperial Innovations Ltd. Appetite-influencing medicaments, WO2006095167. 2006.
   Google Scholar
• Eisai R&D Management Co Ltd. Screening method, US20070054850. 2007.
   Google Scholar
• Eisai R&D Management Co Ltd. Methods of affecting feeding and weight in mammals by administration of relaxin-3, US7638490. 2009.
   Google Scholar
• Eisai R&D Management Co Ltd. Screening method, US20100168014. 2010.
   Google Scholar
• Eisai R&D Management Co Ltd. Peptide having antianxiety activity and screening method therefor, US20090311185. 2009.
   Google Scholar
• National University of Singapore. Stapled peptide agonists and their use in treatment of behavioral disorders, WO2019098945. 2019.
   Google Scholar
• National University of Singapore. Stapled relaxin-3 B-chain peptide antagonists, WO2020231337. 2020.
   Google Scholar
• Research Triangle Institute. Small molecule antagonists for the relaxin-3/RXFP3 system, WO2022192126. 2022.
   Google Scholar
• Kuei C, Sutton S, Bonaventure P, et al. R3(BDelta23 27)R/I5 chimeric peptide, a selective antagonist for GPCR135 and GPCR142 over relaxin receptor LGR7: in vitro and in vivo characterization. J Biol Chem. 2007;282(35):25425–25435. doi: 10.1074/jbc.M701416200
   PubMed Web of Science ®Google Scholar
• DeChristopher B, Park SH, Vong L, et al. Discovery of a small molecule RXFP3/4 agonist that increases food intake in rats upon acute central administration. Bioorg Med Chem Lett. 2019;29(8):991–994. doi: 10.1016/j.bmcl.2019.02.013
   PubMed Web of Science ®Google Scholar
• Guan D, Rahman MT, Gay EA, et al. Indole-containing amidinohydrazones as nonpeptide, dual RXFP3/4 agonists: synthesis, structure-activity relationship, and molecular modeling studies. J Med Chem. 2021;64(24):17866–17886. doi: 10.1021/acs.jmedchem.1c01081
   PubMed Web of Science ®Google Scholar
• Lin G, Feng Y, Cai X, et al. High-throughput screening campaign identified a potential small molecule RXFP3/4 agonist. Molecules. 2021;26(24):7511. doi: 10.3390/molecules26247511
   PubMed Web of Science ®Google Scholar
• Kristensson L, Mayer G, Ploj K, et al. Partial agonist activity of R3(BDelta23-27)R/I5 at RXFP3–investigation of in vivo and in vitro pharmacology. Eur J Pharmacol. 2015;747:123–131. doi: 10.1016/j.ejphar.2014.11.041
   PubMed Web of Science ®Google Scholar
• Kocan M, Sarwar M, Hossain MA, et al. Signalling profiles of H3 relaxin, H2 relaxin and R3(BDelta23-27)R/I5 acting at the relaxin family peptide receptor 3 (RXFP3). Br J Pharmacol. 2014;171(11):2827–2841. doi: 10.1111/bph.12623
   PubMed Web of Science ®Google Scholar
• Gay EA, Guan D, Van Voorhies K, et al. Discovery and characterization of the first nonpeptide antagonists for the relaxin-3/RXFP3 system. J Med Chem. 2022;65(11):7959–7974. doi: 10.1021/acs.jmedchem.2c00508
   PubMed Web of Science ®Google Scholar
• Alvarez-Jaimes L, Sutton SW, Nepomuceno D, et al. In vitro pharmacological characterization of RXFP3 allosterism: an example of probe dependency. PLoS One. 2012;7(2):e30792. doi: 10.1371/journal.pone.0030792
   PubMed Web of Science ®Google Scholar
• Van Voorhies KJ, Liu W, Lovelock DF, et al. Novel RXFP3 negative allosteric modulator RLX-33 reduces alcohol self-administration in rats. J Neurochem. 2023;167(2):204–217. doi: 10.1111/jnc.15949
   PubMed Web of Science ®Google Scholar
• Sharma K, Sharma KK, Sharma A, et al. Peptide-based drug discovery: current status and recent advances. Drug Discov Today. 2023;28(2):103464. doi: 10.1016/j.drudis.2022.103464
   PubMed Web of Science ®Google Scholar
• Wang L, Wang N, Zhang W, et al. Therapeutic peptides: current applications and future directions. Signal Transduct Target Ther. 2022;7(1):48. doi: 10.1038/s41392-022-00904-4
   PubMed Web of Science ®Google Scholar
• Hojo K, Hossain MA, Tailhades J, et al. Development of a single-chain peptide agonist of the relaxin-3 receptor using hydrocarbon stapling. J Med Chem. 2016;59(16):7445–7456. doi: 10.1021/acs.jmedchem.6b00265
   PubMed Web of Science ®Google Scholar
• Melancon BJ, Hopkins CR, Wood MR, et al. Allosteric modulation of seven transmembrane spanning receptors: theory, practice, and opportunities for central nervous system drug discovery. J Med Chem. 2012;55(4):1445–1464. doi: 10.1021/jm201139r
   PubMed Web of Science ®Google Scholar