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

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.

• Authors: Francine Pazini, Ricardo Menegatti, José R Sabino, Carolina H Andrade, Gilda Neves, Stela M K Rates, François Noël, Carlos A M Fraga, Eliezer J Barreiro, Valéria de Oliveira
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 20 Issue 9 Pg. 2888-91 (May 01 2010) ISSN: 1464-3405 [Electronic] England
• PMID: 20363131 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: 2010 Elsevier Ltd. All rights reserved.

Chemical References

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

Topics

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