Discovery of Potent and Brain-Penetrant Inverse Agonists for GPR61, an Orphan G Protein-Coupled Receptor PMID: 41834467

ADC Targets in Oncology

2026-04-10

Discovery of Potent and Brain-Penetrant Inverse Agonists for GPR61, an Orphan G Protein-Coupled Receptor

J Med Chem. 2026 Mar 26;69(6):7393-7404. doi: 10.1021/acs.jmedchem.6c00081.

Ethan L Fisher ¹ , Anne-Marie Dechert Schmitt ¹ , Jamison B Tuttle ² , Ray Unwalla ² , Gabrielle H Lovett ² , Bethany L Kormos ² , Karen J Coffman ¹ , Dahui Zhou ¹ , Michael Moran ¹ , Jade Williams ¹ , Jun Xiao ¹ , Erik A LaChapelle ¹ , Jean-Philippe Fortin ² , Abdul Q Sheikh ² , Kimberly A Stevens ¹ , Jimmy X Kong ² , Emily A G Hughes ² , Ryan M Esquejo ² , Stephanie Joaquim ² , Nalissa L Amar ² , Danielle Archambault ² , Jeonifer Garren ² , Danna Breen ² , Srinath Jagarlapudi ² , Robert Dullea ² , Rebecca E O'Connor ¹ , Erika Koslov-Davino ¹ , Ernesto Callegari ¹ , João M Dias ¹ , Joshua A Lees ¹ , Kris Borzilleri ¹ , Seungil Han ¹ , Jonathan Brooks ² , Felix F Vajdos ¹ , Ashish Goyal ² , Lei Zhang ² , Yuan Zhang ²

Affiliations

Abstract

GPR61 is a class A orphan G protein-coupled receptor (GPCR) that is predominantly expressed in the pituitary gland and appetite-regulating centers of the brain. Genome-wide association analysis, epigenetic analysis, and animal model data have suggested that GPR61 could be a potential therapeutic target for appetite and body weight modulation. Herein, we describe our medicinal chemistry efforts in discovering a class of potent, selective, and brain-penetrant GPR61 inverse agonists. The cryogenic electron microscopy structure of GPR61 bound to compound 15 shows that this class of inverse agonists binds to an induced, intracellular, allosteric pocket and abolishes GPR61 constitutive activity by disrupting its interactions with G protein, representing a novel mode of action of GPCR inverse agonism.