Benzamide bioisosteres incorporating dihydroheteroazole substructures: EPC synthesis and SAR leading to a selective dopamine D4 receptor partial agonist (FAUC 179)

Bioorg Med Chem Lett. 2001 Sep 17;11(18):2533-6. doi: 10.1016/s0960-894x(01)00484-x.

Abstract

Conformationally restricted benzamide bioisosteres were investigated when the chiral phenyldihydroimidazole derivative 4e (FAUC 179) showed strong and highly selective dopamine D4 receptor binding (K(i)high=0.95nM). Mitogenesis experiments indicated partial agonist properties (42%). EPC syntheses of the target compounds of type 4 were performed starting from alpha-amino acids.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biochemistry / methods
  • CHO Cells
  • Cattle
  • Clozapine / pharmacology
  • Cricetinae
  • Cysteine / chemistry
  • Dopamine Antagonists / metabolism
  • Drug Design
  • Humans
  • In Vitro Techniques
  • Indoles / chemistry*
  • Indoles / metabolism
  • Indoles / pharmacology*
  • Magnetic Resonance Spectroscopy
  • Molecular Structure
  • Quinpirole / pharmacology
  • Receptors, Dopamine D2 / agonists*
  • Receptors, Dopamine D2 / metabolism
  • Receptors, Dopamine D4
  • Serine / chemistry
  • Spiperone / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • Threonine / chemistry

Substances

  • DRD4 protein, human
  • Dopamine Antagonists
  • FAUC 179
  • Indoles
  • Receptors, Dopamine D2
  • Receptors, Dopamine D4
  • Quinpirole
  • Threonine
  • Serine
  • Spiperone
  • Clozapine
  • Cysteine