Therapeutic Assessment and Neuroprotective Effects of a Novel G Protein‐Coupled Estrogen Receptor (GPR30/GPER) Agonist

Abstract

The G protein‐coupled estrogen receptor (GPER) has been implicated in the neuroprotective effects of 17β‐estradiol and selective GPER agonist, G‐1. Currently, G‐1 remains the standard for GPER agonists, necessitating the design and identification of novel candidates. Previously, our group synthesized and biologically evaluated a series of GPER antagonists. Modification of an aromatic moiety on the scaffold altered the pharmacological profile from antagonists to agonists. Using a fluorescence‐based binding assay for the classical estrogen receptors, ERa and ERb, we discovered off‐target binding. Due to the similarity in functionalization to estradiol, we hypothesized that the hydrogen bonding abilities of the initial candidate were responsible for the observed off‐target binding. To mitigate off‐target binding, modifications were made to reduce the hydrogen bonding ability. For each resulting candidate, the EC50 value was determined through in vitro biochemical screening. From these studies, we identified a lead compound that exhibited an EC50 value below that of our experimentally determined EC50 value of G‐1. Using E18 rat embryonic hippocampal neurons, the lead compound was shown to increase synaptogenesis. These results suggest that the identified lead compound for GPER may be a potential candidate for neurodegenerative diseases.Support or Funding InformationSaint Louis UniversityThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.