ArticlePloS one2012
In vitro pharmacological characterization of RXFP3 allosterism: an example of probe dependency.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 20 citations in OpenAlex.
- Discovery and Characterization of the First Nonpeptide Antagonists for the Relaxin-3/RXFP3 System.Journal of medicinal chemistry · 2022Article
- High-Throughput Screening Campaign Identified a Potential Small Molecule RXFP3/4 Agonist.Molecules (Basel, Switzerland) · 2021Article
- Orthosteric, Allosteric and Biased Signalling at the Relaxin-3 Receptor RXFP3.Neurochemical research · 2016Article
- International Union of Basic and Clinical Pharmacology. XCV. Recent advances in the understanding of the pharmacology and biological roles of relaxin family peptide receptors 1-4, the receptors for relaxin family peptides.Pharmacological reviews · 2015Review
- Relaxin-3/RXFP3 networks: an emerging target for the treatment of depression and other neuropsychiatric diseases?Frontiers in pharmacology · 2014Review
- Time and dose relationships between schisandrin B- and schisandrae fructus oil-induced hepatotoxicity and the associated elevations in hepatic and serum triglyceride levels in mice.Drug design, development and therapy · 2014Article
- Article
- Targeting the relaxin-3/RXFP3 system: a patent review for the last two decades.Expert opinion on therapeutic patentsReview
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Recent findings suggest that the relaxin-3 neural network may represent a new ascending arousal pathway able to modulate a range of neural circuits including those affecting circadian rhythm and sleep/wake states, spatial and emotional memory, motivation and reward, the response to stress, and feeding and metabolism. Therefore, the relaxin-3 receptor (RXFP3) is a potential therapeutic target for the treatment of various CNS diseases. Here we describe a novel selective RXFP3 receptor positive allosteric modulator (PAM), 3-[3,5-Bis(trifluoromethyl)phenyl]-1-(3,4-dichlorobenzyl)-1-[2-(5-methoxy-1H-indol-3-yl)ethyl]urea (135PAM1). Calcium mobilization and cAMP accumulation assays in cell lines expressing the cloned human RXFP3 receptor show the compound does not directly activate RXFP3 receptor but increases functional responses to amidated relaxin-3 or R3/I5, a chimera of the INSL5 A chain and the Relaxin-3 B chain. 135PAM1 increases calcium mobilization in the presence of relaxin-3(NH2) and R3/I5(NH2) with pEC50 values of 6.54 (6.46 to 6.64) and 6.07 (5.94 to 6.20), respectively. In the cAMP accumulation assay, 135PAM1 inhibits the CRE response to forskolin with a pIC50 of 6.12 (5.98 to 6.27) in the presence of a probe (10 nM) concentration of relaxin-3(NH2). 135PAM1 does not compete for binding with the orthosteric radioligand, [(125)I] R3I5 (amide), in membranes prepared from cells expressing the cloned human RXFP3 receptor. 135PAM1 is selective for RXFP3 over RXFP4, which also responds to relaxin-3. However, when using the free acid (native) form of relaxin-3 or R3/I5, 135PAM1 doesn't activate RXFP3 indicating that the compound's effect is probe dependent. Thus one can exchange the entire A-chain of the probe peptide while retaining PAM activity, but the state of the probe's c-terminus is crucial to allosteric activity of the PAM. These data demonstrate the existence of an allosteric site for modulation of this GPCR as well as the subtlety of changes in probe molecules that can affect allosteric modulation of RXFP3.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.