Design, synthesis, and evaluation of indolebutylamines as a novel class of selective dopamine D3 receptor ligands

Chem Biol Drug Des. 2013 Sep;82(3):326-35. doi: 10.1111/cbdd.12158.

Abstract

A series of indolebutylamine derivatives were designed, synthesized, and evaluated as a novel class of selective ligands for the dopamine 3 receptor. The most potent compound 11q binds to dopamine 3 receptor with a Ki value of 124 nm and displays excellent selectivity over the dopamine 1 receptor and dopamine 2 receptor. Investigation based on structural information indicates that site S182 located in extracellular loop 2 may account for high selectivity of compounds. Interaction models of the dopamine 3 receptor-11q complex and structure-activity relationships were discussed by integrating all available experimental and computational data with the eventual aim to discover potent and selective ligands to dopamine 3 receptor.

Keywords: dopamine 3 receptor; indolebutylamine; pharmacophore model; selectivity; structure-activity relationship.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetanilides / chemical synthesis*
  • Acetanilides / chemistry
  • Acetanilides / metabolism
  • Amino Acid Sequence
  • Binding Sites
  • Butylamines / chemical synthesis
  • Butylamines / chemistry*
  • Butylamines / metabolism
  • Catalytic Domain
  • Dopamine Antagonists / chemical synthesis*
  • Dopamine Antagonists / chemistry
  • Dopamine Antagonists / metabolism
  • Dopamine D2 Receptor Antagonists
  • Drug Design*
  • HEK293 Cells
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / chemistry*
  • Indoles / metabolism
  • Ligands
  • Molecular Docking Simulation
  • Molecular Sequence Data
  • Protein Binding
  • Receptors, Dopamine D1 / antagonists & inhibitors
  • Receptors, Dopamine D1 / genetics
  • Receptors, Dopamine D1 / metabolism
  • Receptors, Dopamine D2 / genetics
  • Receptors, Dopamine D2 / metabolism
  • Receptors, Dopamine D3 / antagonists & inhibitors*
  • Receptors, Dopamine D3 / genetics
  • Receptors, Dopamine D3 / metabolism
  • Structure-Activity Relationship

Substances

  • Acetanilides
  • Butylamines
  • Dopamine Antagonists
  • Dopamine D2 Receptor Antagonists
  • Indoles
  • Ligands
  • N-cyclohexyl-2-(4-(4-(5-fluoro-1H-indol-3-yl)butyl)piperazin-1-yl)-N-(2-methoxyphenyl)acetamide
  • Receptors, Dopamine D1
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3
  • indole