Cyanoindole derivatives as highly selective dopamine D(4) receptor partial agonists: solid-phase synthesis, binding assays, and functional experiments

J Med Chem. 2000 Nov 16;43(23):4563-9. doi: 10.1021/jm0009989.

Abstract

Traceless linking of diethoxymethyl (DEM)-protected 5- and 6-cyanoindoles and subsequent incorporation of phenylpiperazine derivatives led to the 2- and 3-piperazinylmethyl-substituted cyanoindoles 3a-m. Dopamine receptor binding studies on the final products 3a-m clearly indicated strong and selective recognition of the D(4) subtype which is known as a promising target for the treatment of neuropsychiatric disorders. The most interesting binding properties were observed for the 2-aminomethyl-5-cyanoindoles FAUC 299 (3f) and FAUC 316 (3j) (K(i) = 0.52 and 1.0 nM, respectively) when the fluoro derivative 3j proved extraordinary selectivity over D(1), D(2long), D(2short), and D(3) (>8600). To determine ligand efficacy, mitogenesis experiments were performed indicating partial agonist effects for the test compounds 3f,j (35% and 30%, when compared to the full agonist quinpirole).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Central Nervous System Agents / chemical synthesis*
  • Central Nervous System Agents / chemistry
  • Central Nervous System Agents / metabolism
  • Central Nervous System Agents / pharmacology
  • Corpus Striatum / metabolism
  • Cricetinae
  • Dopamine Agonists / chemical synthesis*
  • Dopamine Agonists / chemistry
  • Dopamine Agonists / metabolism
  • Dopamine Agonists / pharmacology
  • Humans
  • In Vitro Techniques
  • Indoles / chemical synthesis*
  • Indoles / chemistry
  • Indoles / metabolism
  • Indoles / pharmacology
  • Ligands
  • Mitogens / chemical synthesis
  • Mitogens / chemistry
  • Mitogens / metabolism
  • Mitogens / pharmacology
  • Piperazines / chemical synthesis*
  • Piperazines / chemistry
  • Piperazines / metabolism
  • Piperazines / pharmacology
  • Radioligand Assay
  • Receptors, Dopamine D2 / metabolism*
  • Receptors, Dopamine D4
  • Structure-Activity Relationship
  • Thymidine / metabolism

Substances

  • Central Nervous System Agents
  • DRD4 protein, human
  • Dopamine Agonists
  • FAUC 316
  • Indoles
  • Ligands
  • Mitogens
  • Piperazines
  • Receptors, Dopamine D2
  • Receptors, Dopamine D4
  • Thymidine
  • FAUC 299