Design of new dopamine D2 receptor ligands: biosynthesis and pharmacological evaluation of the hydroxylated metabolite of LASSBio-581

Bioorg Med Chem Lett. 2010 May 1;20(9):2888-91. doi: 10.1016/j.bmcl.2010.03.034. Epub 2010 Mar 10.

Abstract

LASSBio-581 is a N-phenylpiperazine derivative designed for the treatment of schizophrenia. In this study, four strains of filamentous fungi were screened for their capabilities to biotransform LASSBio-581. Cunninghamella echinulata ATCC 9244 was chosen to scale up the biosynthesis of the p-hydroxylated metabolite of LASSBio-581. The chemical structure of the metabolite was confirmed by NMR, LC-MS and X-ray crystallography. Binding studies performed on brain homogenate indicated that the p-hydroxylated metabolite can be considered more selective for dopamine receptors than LASSBio-581, and, therefore, can be used to design new selective dopamine inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Crystallography, X-Ray
  • Cunninghamella / metabolism
  • Dopamine D2 Receptor Antagonists*
  • Drug Design
  • Drug Evaluation, Preclinical
  • Hydroxylation
  • Ligands*
  • Molecular Conformation
  • Piperazines / chemistry
  • Piperazines / metabolism*
  • Piperazines / pharmacology
  • Protein Binding
  • Receptors, Dopamine D2 / metabolism

Substances

  • Dopamine D2 Receptor Antagonists
  • LASSBio-581
  • Ligands
  • Piperazines
  • Receptors, Dopamine D2