Synthesis of Bitopic Ligands as Potent Dopamine D2 Receptor Agonists

ChemMedChem. 2022 Feb 16;17(4):e202100681. doi: 10.1002/cmdc.202100681. Epub 2021 Dec 21.

Abstract

In this study, we designed and synthesized twelve bitopic ligands as dopamine D2 receptor (D2 R) agonists. The forskolin-induced cAMP accumulation assay revealed that all the finial compounds are able to activate D2 R. Furthermore, bitopic ligand N-((trans)-4-(((2,3-dihydro-1H-inden-2-yl)(propyl)amino)methyl)cyclo-hexyl)-1H-pyrrolo[2,3-b]pyridine-2-carboxamide (11 b) showed 21-fold higher potency than lead compound propyl aminoindane (2) and 17-fold higher subtype selectivity for D2 R over D4 R, indicating that the optimal length of spacer affects the D2 R functionality. Molecular modeling study exhibited that 11 b formed an electrostatic interaction and two H-bonds with amino acid Asp114, which contributes significantly to the D2 R functional activity. Taken together, we discovered a bitopic ligand 11 b as potent D2 R agonist, which may be used as a tool compound for further study.

Keywords: D2R agonists; bitopic ligands; dopamine D2 receptor; subtype selectivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Humans
  • Indans / chemistry
  • Indans / pharmacology*
  • Ligands
  • Models, Molecular
  • Molecular Structure
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Receptors, Dopamine D2 / agonists*
  • Structure-Activity Relationship

Substances

  • Indans
  • Ligands
  • Pyridines
  • Receptors, Dopamine D2