Identification of small molecule that selectively modulate Ghrelin receptor (GHSR1a) b-arrestin signaling as a new therapeutic approach for the treatment of addiction

National Center For Advancing Translational Sciences

Investigators

Abstract

During this period, the project team focused on structure activity relationship studies and lead optimization. Ghrelin receptor pharmacology was characterized by measuring G protein activation, B-arrestin recruitment, and endosomal trafficking. We also have progressed toward the production of proteins for cryo-EM and the production of a humanized mouse. Binding to the receptor is being assessed using a combination of in silico modeling, mutagenesis, and biophysical approaches. Structure-activity relationship studies to improve the potency and metabolic properties of the lead molecules are in progress, having already truly selective/bias analogues with reasonable potency. To continue characterization of the lead compound and analogues, the collaborating laboratories have formed an interdisciplinary team with extensive expertise in drug discovery, biochemical and behavioral assays of GPCRs, and testing of drugs in animal models of addictive behaviors in wild type and genetically modified mice.