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

• Published in: Bioorganic & medicinal chemistry letters Vol. 20; no. 9; pp. 2888 - 2891
• Main Authors: Pazini, Francine, Menegatti, Ricardo, Sabino, José R., Andrade, Carolina H., Neves, Gilda, Rates, Stela M.K., Noël, François, Fraga, Carlos A.M., Barreiro, Eliezer J., de Oliveira, Valéria
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier Ltd 01-05-2010; Elsevier
• Subjects: Antipsychotic prototype; Bioconversions. Hemisynthesis; Biological and medical sciences; Biosynthesis; Biotechnology; Brain; Catecholaminergic system; Crystallography, X-Ray; Cunninghamella - metabolism; Cunninghamella echinulata; Dopamine D2 Receptor Antagonists; Dopamine D2 receptor ligands; Drug Design; Drug Evaluation, Preclinical; Fundamental and applied biological sciences. Psychology; Hydroxylation; LASSBio-581; Ligands; Medical sciences; Methods. Procedures. Technologies; Microbial hydroxylation; Molecular Conformation; Neuropharmacology; Neurotransmitters. Neurotransmission. Receptors; Pharmacology. Drug treatments; Piperazines - chemistry; Piperazines - metabolism; Piperazines - pharmacology; Protein Binding; Psycholeptics: tranquillizer, neuroleptic; Psychology. Psychoanalysis. Psychiatry; Psychopharmacology; Receptors, Dopamine D2 - metabolism; Microbial hydroxylation; LASSBio-581; Cunninghamella echinulata; Biosynthesis; Dopamine D2 receptor ligands; Antipsychotic prototype; Five membered ring; Zygomycota; Hydroxylation; Cunninghamella; Nitrogen heterocycle; Metabolite; Psychotropic; In vitro; Fungi; D2 Dopamine receptor; Chlorine Organic compounds; Six membered ring; Piperidine derivatives; Affinity; Antipsychotic; Antagonist; Chemical synthesis; Enzymatic reaction
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2010.03.034

The biosynthesis of the
p-hydroxylated metabolite of LASSBio-581 by
Cunninghamella echinulata and its pharmacological evaluation is reported.
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.