Discovery of Potent and Brain-Penetrant Inverse Agonists for GPR61, an Orphan G Protein-Coupled Receptor
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 <b>15</b> 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.
Authors
- Srinath Jagarlapudi
- Danna M. Breen (ORCID: https://orcid.org/0000-0002-6460-8555)
- Jason Williams (ORCID: https://orcid.org/0000-0002-3804-2594)
- Kris A. Borzilleri
- Denis Archambault (ORCID: https://orcid.org/0000-0001-9409-5140)
- J.C. Brooks (ORCID: https://orcid.org/0000-0003-3335-6209)
- Emily Hughes (ORCID: https://orcid.org/0000-0003-1860-5182)
- Ryan M. Esquejo (ORCID: https://orcid.org/0009-0003-3996-8318)
- Ethan L. Fisher (ORCID: https://orcid.org/0000-0002-8700-5108)
- Karen J. Coffman (ORCID: https://orcid.org/0000-0001-6164-7500)
- Stephanie Joaquim
- Erik LaChapelle
- Jeonifer Garren
- Jamison B. Tuttle (ORCID: https://orcid.org/0009-0002-7201-7074)
- Joshua A. Lees (ORCID: https://orcid.org/0000-0001-7421-6881)
- Robert Dullea (ORCID: https://orcid.org/0000-0002-7946-2034)
- Ray Unwalla (ORCID: https://orcid.org/0000-0002-5789-7336)
- Jimmy Kong
- Seungil Han (ORCID: https://orcid.org/0000-0002-1070-3880)
- Bethany L. Kormos (ORCID: https://orcid.org/0000-0003-2298-9369)
- Abdul Q. Sheikh
- Erika Koslov-Davino
- Kimberly A. Stevens (ORCID: https://orcid.org/0000-0001-5178-128X)
- F.F. Vajdos (ORCID: https://orcid.org/0000-0002-8256-2087)
- L. Lena Zhang
- Rebecca E. O’Connor (ORCID: https://orcid.org/0000-0002-4270-970X)
- Ernesto Callegari (ORCID: https://orcid.org/0000-0002-8429-0724)
- João M. Dias (ORCID: https://orcid.org/0000-0003-3336-2334)
- Yuan Zhang (ORCID: https://orcid.org/0000-0002-3881-6537)
- Michael Moran (ORCID: https://orcid.org/0000-0003-1712-9444)
- Duo Zhou
- N. Amar
- Gabrielle H. Lovett
- Jean-Philippe Fortin
- Ashish Goyal
- Jun Xiao
- Anne-Marie Dechert Schmitt
Institutions
- Pfizer (United States) (US)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2026-03-16
- DOI
- https://doi.org/10.1021/acs.jmedchem.6c00081
- Primary Topic
- Receptor Mechanisms and Signaling
- Type
- article
- Field-Weighted Citation Impact
- 0.00