Discovery of a functionally selective ghrelin receptor (GHSR 1a ) ligand for modulating brain dopamine

J. D. Gross, D. W. Kim, Y. Zhou, D. Jansen, L. M. Slosky, N. B. Clark, C. R. Ray, X. Hu, N. Southall, A. Wang, X. Xu, E. Barnaeva, W. C. Wetsel, M. Ferrer, J. J. Marugan, M. G. Caron, L. S. Barak, K. Toth

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

The growth hormone secretagogue receptor-1a (GHSR 1a) is the cognate G protein-coupled receptor (GPCR) for the peptide hormone ghrelin. GHSR 1a is a promising therapeutic target for a wide range of metabolic, age-related, and central nervous system (CNS)-based conditions. In addition, growing evidence supports that GHSR 1a is a modulator of dopamine (DA) homeostasis and is neuroprotective within brain DA circuits. GHSR 1a signaling originates from pharmacologically separable G protein- and β-arrestin (βarr)-dependent pathways, and consequently, GHSR 1a-mediated physiological responses depend upon their distinctive signaling contributions. Thus, when treating disorders of disrupted DA homeostasis, a pharmacological strategy that modulates biased GHSR 1a signaling may uncouple desired therapeutic outcomes from unwanted side effects. Here, we report the discovery of a small molecule GHSR 1a agonist, N8279 (NCATS-SM8864), functionally selective for G protein signaling. Comprehensive pharmacological characterization reveals that N8279 elicits potent Gα q activity at the apo- and ghrelin-bound GHSR 1a. Further biochemical analysis and molecular modeling demonstrate that N8279 signaling requires the extracellular domain of GHSR 1a, especially extracellular loop 2. Collectively, these findings suggest that N8279 possesses an extended binding mode into the extracellular vestibule of the GHSR 1a that preferentially favors Gα q signaling over alternative G proteins and βarr2-dependent cellular responses. Critically, N8279 is brain-penetrant in mice, exhibits CNS stability, and attenuates dysfunctional DA-mediated behaviors in both genetic and pharmacological mouse models of hyperdopaminergia. Our findings provide insight into the mechanisms governing GPCR functional selectivity and emphasize how biased ligand drug development can produce novel GHSR 1a pharmacotherapeutics to treat pathological disruptions of brain DA homeostasis.

Original languageEnglish (US)
Article numbere2112397119
Pages (from-to)e2112397119
JournalProceedings of the National Academy of Sciences
Volume119
Issue number10
DOIs
StatePublished - Mar 8 2022

Bibliographical note

Funding Information:
ACKNOWLEDGMENTS. We thank Wendy Roberts for the maintenance of the DAT KO and C57BL/6J mouse colonies (Duke University). We also thank Yushi Bai and Lauren Rochelle for performing initial GHSR1a radioligand binding and signaling assays with the hit compounds and the commercial compound library, respectively. We thank the Mouse Behavioral and Neuroendocrine Analysis Core Facility staff for running the behavioral sensitization experiments, with Dr. Ramona M. Rodriguiz statistically analyzing these data (Duke University). Some of the equipment and software used in the behavioral experiments were purchased with a grant from the North Carolina Biotechnology Center. This work has been funded by NIH grants from the National Institute on Drug Abuse, F32DA051139 (J.D.G.), U18DA052417 (L.S.B. and M.G.C.), and P30DA029925 (M.G.C., L.S.B., and K.T.); National Institute of Mental Health grant R37MH073853 (M.G.C.), and National Center for Advancing Translational Sciences grant ZIATR000083 (J.J.M.).

Funding Information:
We thank Wendy Roberts for the maintenance of the DAT KO and C57BL/6J mouse colonies (Duke University). We also thank Yushi Bai and Lauren Rochelle for performing initial GHSR1a radioligand binding and signaling assays with the hit compounds and the commercial compound library, respectively. We thank the Mouse Behavioral and Neuroendocrine Analysis Core Facility staff for running the behavioral sensitization experiments, with Dr. Ramona M. Rodriguiz statistically analyzing these data (Duke University). Some of the equipment and software used in the behavioral experiments were purchased with a grant from the North Carolina Biotechnology Center. This work has been funded by NIH grants from the National Institute on Drug Abuse, F32DA051139 (J.D.G.), U18DA052417 (L.S.B. and M.G.C.), and P30DA029925 (M.G.C., L.S.B., and K.T.); National Institute of Mental Health grant R37MH073853 (M.G.C.), and National Center for Advancing Translational Sciences grant ZIATR000083 (J.J.M.).

Publisher Copyright:
© 2022 National Academy of Sciences. All rights reserved.

Keywords

  • GPCR
  • NCATS-SM8864
  • dopamine
  • functional selectivity
  • ghrelin
  • Male
  • Receptors, Ghrelin/genetics
  • Mice, Knockout
  • Animals
  • GTP-Binding Protein alpha Subunits, Gq-G11/genetics
  • Mice
  • Dopamine/genetics
  • Brain/metabolism

PubMed: MeSH publication types

  • Journal Article

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