Design of new dopamine D2 receptor ligands: biosynthesis and pharmacological evaluation of the hydroxylated metabolite of LASSBio-581.
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.
Pazini
Francine
F
Laboratório de Bioconversão, Faculdade de Farmácia, Universidade Federal de Goiás, Goiânia, GO, Brazil.
Menegatti
Ricardo
R
Sabino
José R
JR
Andrade
Carolina H
CH
Neves
Gilda
G
Rates
Stela M K
SM
Noël
François
F
Fraga
Carlos A M
CA
Barreiro
Eliezer J
EJ
de Oliveira
Valéria
V
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
D065127:Dopamine D2 Receptor Antagonists; C490224:LASSBio-581; D008024:Ligands; D010879:Piperazines; D017448:Receptors, Dopamine D2