Novel Bivalent Ligands Based on the Sumanirole Pharmacophore Reveal Dopamine D2 Receptor (D2R) Biased Agonism.
J Med Chem
; 60(7): 2890-2907, 2017 04 13.
Article
em En
| MEDLINE
| ID: mdl-28300398
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 ß-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 ß-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 ß-arrestin recruitment in D2R-BRET functional assays.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Benzimidazóis
/
Receptores de Dopamina D2
/
Agonistas de Dopamina
Limite:
Humans
Idioma:
En
Ano de publicação:
2017
Tipo de documento:
Article