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

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 G_i/o-proteins, while reducing or suppressing potency and efficacy toward β-arrestin recruitment. Compound 19 was identified as a new lead for its

SUBMITTER: Bonifazi A 

PROVIDER: S-EPMC7594663 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature