In vitro pharmacological characterization of RXFP3 allosterism: an example of probe dependency.

PloS One
Lily Alvarez-JaimesPascal Bonaventure

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) co...Continue Reading

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Citations

Dec 19, 2013·PloS One·Fazel ShabanpoorMohammed Akhter Hossain
Sep 21, 2013·Drug Discovery Today. Technologies·Stephan SchannPascal Neuville
Jun 26, 2012·Pharmacology & Therapeutics·Christa E MüllerYounis Baqi
Aug 22, 2015·Neurochemical Research·Martina KocanRoger J Summers
Feb 13, 2013·Medicinal Research Reviews·Valeria CernaroMichele Buemi
Jan 11, 2013·Physiological Reviews·R A D BathgateR J Summers
Aug 11, 2017·Journal of Medicinal Chemistry·Mario SchubertAnnette G Beck-Sickinger

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Methods Mentioned

BETA
amidation

Software Mentioned

Prism
GraphPad Prism
GraphPad

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