Development of a bivalent dopamine D₂ receptor agonist

J Med Chem. 2011 Nov 24;54(22):7911-9. doi: 10.1021/jm2009919. Epub 2011 Oct 31.

Abstract

Bivalent D₂ agonists may function as useful molecular probes for the discovery of novel neurological therapeutics. On the basis of our recently developed bivalent dopamine D₂ receptor antagonists of type 1, the bivalent agonist 2 was synthesized when a spacer built from 22 atoms was employed. Compared to the monovalent control compound 6 containing a capped spacer, the bis-aminoindane derivative 2 revealed substantial steepening of the competition curve, indicating a bivalent binding mode. Dimer-specific Hill slopes were not a result of varying functional properties because both the dopaminergic 2 and the monovalent control agent 6 proved to be D₂ agonists substantially inhibiting cAMP accumulation and inducing D₂ receptor internalization. Investigation of the heterobivalent ligands 8 and 9, containing an agonist and a phenylpiperazine-based antagonist pharmacophore, revealed moderate steepening of the displacement curves and antagonist to very weak partial agonist properties.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzamides / chemical synthesis
  • Benzamides / chemistry
  • Benzamides / pharmacology
  • Binding, Competitive
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Cyclic AMP / biosynthesis
  • Drug Partial Agonism
  • HEK293 Cells
  • Humans
  • Ligands
  • Models, Molecular
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / pharmacology
  • Protein Multimerization
  • Radioligand Assay
  • Receptors, Dopamine D2 / agonists*
  • Receptors, Dopamine D2 / metabolism
  • Signal Transduction
  • Structure-Activity Relationship
  • Swine
  • Triazoles / chemical synthesis*
  • Triazoles / chemistry
  • Triazoles / pharmacology

Substances

  • Benzamides
  • Ligands
  • Piperazines
  • Receptors, Dopamine D2
  • Triazoles
  • Cyclic AMP