Novel Bivalent Ligands Based on the Sumanirole Pharmacophore Reveal Dopamine D2 Receptor (D2R) Biased Agonism

J Med Chem. 2017 Apr 13;60(7):2890-2907. doi: 10.1021/acs.jmedchem.6b01875. Epub 2017 Mar 16.

Abstract

The development of bivalent ligands has attracted interest as a way to potentially improve the selectivity and/or affinity for a specific receptor subtype. The ability to bind two distinct receptor binding sites simultaneously can allow the selective activation of specific G-protein dependent or β-arrestin-mediated cascade pathways. Herein, we developed an extended SAR study using sumanirole (1) as the primary pharmacophore. We found that substitutions in the N-1- and/or N-5-positions, physiochemical properties of those substituents, and secondary aromatic pharmacophores can enhance agonist efficacy for the cAMP inhibition mediated by Gi/o-proteins, while reducing or suppressing potency and efficacy toward β-arrestin recruitment. Compound 19 was identified as a new lead for its selective D2 G-protein biased agonism with an EC50 in the subnanomolar range. Structure-activity correlations were observed between substitutions in positions N-1 and/or N-5 of 1 and the capacity of the new bivalent compounds to selectively activate G-proteins versus β-arrestin recruitment in D2R-BRET functional assays.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Intramural

MeSH terms

  • Benzimidazoles / chemistry*
  • Benzimidazoles / pharmacology*
  • Cyclic AMP / metabolism
  • Dopamine Agonists / chemistry*
  • Dopamine Agonists / pharmacology*
  • GTP-Binding Proteins / metabolism
  • HEK293 Cells
  • Humans
  • Receptors, Dopamine D2 / agonists*
  • Receptors, Dopamine D2 / metabolism
  • Structure-Activity Relationship
  • beta-Arrestins / metabolism

Substances

  • Benzimidazoles
  • Dopamine Agonists
  • Receptors, Dopamine D2
  • beta-Arrestins
  • U 95666E
  • Cyclic AMP
  • GTP-Binding Proteins