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D2 Dopamine Receptor G Protein-Biased Partial Agonists Based on Cariprazine.

Publication ,  Journal Article
Shen, Y; McCorvy, JD; Martini, ML; Rodriguiz, RM; Pogorelov, VM; Ward, KM; Wetsel, WC; Liu, J; Roth, BL; Jin, J
Published in: J Med Chem
May 9, 2019

Functionally selective G protein-coupled receptor ligands are valuable tools for deciphering the roles of downstream signaling pathways that potentially contribute to therapeutic effects versus side effects. Recently, we discovered both Gi/o-biased and β-arrestin2-biased D2 receptor agonists based on the Food and Drug Administration (FDA)-approved drug aripiprazole. In this work, based on another FDA-approved drug, cariprazine, we conducted a structure-functional selectivity relationship study and discovered compound 38 (MS1768) as a potent partial agonist that selectively activates the Gi/o pathway over β-arrestin2. Unlike the dual D2R/D3R partial agonist cariprazine, compound 38 showed selective agonist activity for D2R over D3R. In fact, compound 38 exhibited potent antagonism of dopamine-stimulated β-arrestin2 recruitment. In our docking studies, compound 38 directly interacts with S1935.42 on TM5 but has no interactions with extracellular loop 2, which appears to be in contrast to the binding poses of D2R β-arrestin2-biased ligands. In in vivo studies, compound 38 showed high D2R receptor occupancy in mice and effectively inhibited phencyclidine-induced hyperlocomotion.

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Published In

J Med Chem

DOI

EISSN

1520-4804

Publication Date

May 9, 2019

Volume

62

Issue

9

Start / End Page

4755 / 4771

Location

United States

Related Subject Headings

  • beta-Arrestin 2
  • Structure-Activity Relationship
  • Signal Transduction
  • Receptors, Dopamine D2
  • Piperazines
  • Molecular Structure
  • Molecular Docking Simulation
  • Mice, Inbred C57BL
  • Methylurea Compounds
  • Medicinal & Biomolecular Chemistry
 

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Shen, Y., McCorvy, J. D., Martini, M. L., Rodriguiz, R. M., Pogorelov, V. M., Ward, K. M., … Jin, J. (2019). D2 Dopamine Receptor G Protein-Biased Partial Agonists Based on Cariprazine. J Med Chem, 62(9), 4755–4771. https://doi.org/10.1021/acs.jmedchem.9b00508
Shen, Yudao, John D. McCorvy, Michael L. Martini, Ramona M. Rodriguiz, Vladimir M. Pogorelov, Karen M. Ward, William C. Wetsel, Jing Liu, Bryan L. Roth, and Jian Jin. “D2 Dopamine Receptor G Protein-Biased Partial Agonists Based on Cariprazine.J Med Chem 62, no. 9 (May 9, 2019): 4755–71. https://doi.org/10.1021/acs.jmedchem.9b00508.
Shen Y, McCorvy JD, Martini ML, Rodriguiz RM, Pogorelov VM, Ward KM, et al. D2 Dopamine Receptor G Protein-Biased Partial Agonists Based on Cariprazine. J Med Chem. 2019 May 9;62(9):4755–71.
Shen, Yudao, et al. “D2 Dopamine Receptor G Protein-Biased Partial Agonists Based on Cariprazine.J Med Chem, vol. 62, no. 9, May 2019, pp. 4755–71. Pubmed, doi:10.1021/acs.jmedchem.9b00508.
Shen Y, McCorvy JD, Martini ML, Rodriguiz RM, Pogorelov VM, Ward KM, Wetsel WC, Liu J, Roth BL, Jin J. D2 Dopamine Receptor G Protein-Biased Partial Agonists Based on Cariprazine. J Med Chem. 2019 May 9;62(9):4755–4771.
Journal cover image

Published In

J Med Chem

DOI

EISSN

1520-4804

Publication Date

May 9, 2019

Volume

62

Issue

9

Start / End Page

4755 / 4771

Location

United States

Related Subject Headings

  • beta-Arrestin 2
  • Structure-Activity Relationship
  • Signal Transduction
  • Receptors, Dopamine D2
  • Piperazines
  • Molecular Structure
  • Molecular Docking Simulation
  • Mice, Inbred C57BL
  • Methylurea Compounds
  • Medicinal & Biomolecular Chemistry