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Discovery of a functionally selective ghrelin receptor (GHSR1a) ligand for modulating brain dopamine.

Publication ,  Journal Article
Gross, JD; Kim, DW; Zhou, Y; Jansen, D; Slosky, LM; Clark, NB; Ray, CR; Hu, X; Southall, N; Wang, A; Xu, X; Barnaeva, E; Wetsel, WC; Toth, K ...
Published in: Proc Natl Acad Sci U S A
March 8, 2022
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SignificanceThe modulation of growth hormone secretagogue receptor-1a (GHSR1a) signaling is a promising strategy for treating brain conditions of metabolism, aging, and addiction. GHSR1a activation results in pleiotropic physiological outcomes through distinct and pharmacologically separable G protein- and β-arrestin (βarr)-dependent signaling pathways. Thus, pathway-selective modulation can enable improved pharmacotherapeutics that can promote therapeutic efficacy while mitigating side effects. Here, we describe the discovery of a brain-penetrant small molecule, N8279 (NCATS-SM8864), that biases GHSR1a conformations toward Gαq activation and reduces aberrant dopaminergic behavior in mice. N8279 represents a promising chemical scaffold to advance the development of better treatments for GHSR1a-related brain disorders involving the pathological dysregulation of dopamine.

Duke Scholars

William Christopher Wetsel
Author William Christopher Wetsel Psychiatry & Behavioral Sciences, Behavioral Medicine & Neur ...
Lawrence Simeon Barak
Author Lawrence Simeon Barak Cell Biology
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Published In

Proc Natl Acad Sci U S A

DOI

10.1073/pnas.2112397119

EISSN

1091-6490

Publication Date

March 8, 2022

Volume

119

Issue

10

Start / End Page

e2112397119

Location

United States

Related Subject Headings

  • Receptors, Ghrelin
  • Mice, Knockout
  • Mice
  • Male
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Dopamine
  • Brain
  • Animals
 

Citation

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Gross, J. D., Kim, D. W., Zhou, Y., Jansen, D., Slosky, L. M., Clark, N. B., … Toth, K. (2022). Discovery of a functionally selective ghrelin receptor (GHSR1a) ligand for modulating brain dopamine. Proc Natl Acad Sci U S A, 119(10), e2112397119. https://doi.org/10.1073/pnas.2112397119
Gross, J. D., D. W. Kim, Y. Zhou, D. Jansen, L. M. Slosky, N. B. Clark, C. R. Ray, et al. “Discovery of a functionally selective ghrelin receptor (GHSR1a) ligand for modulating brain dopamine.” Proc Natl Acad Sci U S A 119, no. 10 (March 8, 2022): e2112397119. https://doi.org/10.1073/pnas.2112397119.
Gross JD, Kim DW, Zhou Y, Jansen D, Slosky LM, Clark NB, et al. Discovery of a functionally selective ghrelin receptor (GHSR1a) ligand for modulating brain dopamine. Proc Natl Acad Sci U S A. 2022 Mar 8;119(10):e2112397119.
Gross, J. D., et al. “Discovery of a functionally selective ghrelin receptor (GHSR1a) ligand for modulating brain dopamine.” Proc Natl Acad Sci U S A, vol. 119, no. 10, Mar. 2022, p. e2112397119. Pubmed, doi:10.1073/pnas.2112397119.
Gross JD, Kim DW, Zhou Y, Jansen D, Slosky LM, Clark NB, Ray CR, Hu X, Southall N, Wang A, Xu X, Barnaeva E, Wetsel WC, Ferrer M, Marugan JJ, Caron MG, Barak LS, Toth K. Discovery of a functionally selective ghrelin receptor (GHSR1a) ligand for modulating brain dopamine. Proc Natl Acad Sci U S A. 2022 Mar 8;119(10):e2112397119.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

10.1073/pnas.2112397119

EISSN

1091-6490

Publication Date

March 8, 2022

Volume

119

Issue

10

Start / End Page

e2112397119

Location

United States

Related Subject Headings

  • Receptors, Ghrelin
  • Mice, Knockout
  • Mice
  • Male
  • GTP-Binding Protein alpha Subunits, Gq-G11
  • Dopamine
  • Brain
  • Animals