title: 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.affiliation: Laboratório de Bioconversão, Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, GO, Brazil.
authors.forename: Francine
authors.initials: F
authors.lastname: Pazini
authors.forename: Ricardo
authors.initials: R
authors.lastname: Menegatti
authors.forename: José R
authors.initials: JR
authors.lastname: Sabino
authors.forename: Carolina H
authors.initials: CH
authors.lastname: Andrade
authors.forename: Gilda
authors.initials: G
authors.lastname: Neves
authors.forename: Stela M K
authors.initials: SM
authors.lastname: Rates
authors.forename: François
authors.initials: F
authors.lastname: Noël
authors.forename: Carlos A M
authors.initials: CA
authors.lastname: Fraga
authors.forename: Eliezer J
authors.initials: EJ
authors.lastname: Barreiro
authors.forename: Valéria
authors.initials: V
authors.lastname: de Oliveira
mesh_terms: D018360:Crystallography, X-Ray; D020093:Cunninghamella / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006900:Hydroxylation; D008024:Ligands; D008968:Molecular Conformation; D010879:Piperazines / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D011485:Protein Binding; D017448:Receptors, Dopamine D2 / Q000378:metabolism
chemical_list: D065127:Dopamine D2 Receptor Antagonists; C490224:LASSBio-581; D008024:Ligands; D010879:Piperazines; D017448:Receptors, Dopamine D2