Fused azaindole derivatives: molecular design, synthesis and in vitro pharmacology leading to the preferential dopamine D3 receptor agonist FAUC 725

Bioorg Med Chem Lett. 2002 Sep 2;12(17):2377-80. doi: 10.1016/s0960-894x(02)00390-6.

Abstract

Computational studies based on the similarity of molecular electrostatic potential maps initiated the synthesis of the tricyclic target compounds 1 (FAUC 725) and 2. Receptor binding studies at the dopamine receptor subtypes D1, D2(long), D2(short), D3 and D4 showed that the azaindole 1 revealed D3 affinity (K(i)=0.54 nM) comparable to the lead pramipexole and enhanced selectivity over D2 and D4. Mitogenesis experiments indicated substantial intrinsic activity for the D3 selective dipropylamine 1. Based on the structure of (S)-3-PPP, bioisosteric replacement and conformational restriction leading to the test compound 2 was not fruitful.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aza Compounds / chemical synthesis
  • Aza Compounds / pharmacology
  • Dopamine Agonists / chemical synthesis*
  • Drug Design*
  • Heterocyclic Compounds, 3-Ring / chemical synthesis*
  • Heterocyclic Compounds, 3-Ring / pharmacology
  • Humans
  • Indoles / chemical synthesis*
  • Indoles / pharmacology
  • Models, Molecular
  • Protein Binding
  • Receptors, Dopamine D2 / agonists*
  • Receptors, Dopamine D3
  • Sensitivity and Specificity
  • Static Electricity
  • Structure-Activity Relationship

Substances

  • Aza Compounds
  • DRD3 protein, human
  • Dopamine Agonists
  • FAUC 725
  • Heterocyclic Compounds, 3-Ring
  • Indoles
  • Receptors, Dopamine D2
  • Receptors, Dopamine D3