Advanced search
Start date
(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Evaluation of Functional Selectivity of Haloperidol, Clozapine, and LASSBio-579, an Experimental Compound With Antipsychotic-Like Actions in Rodents, at G Protein and Arrestin Signaling Downstream of the Dopamine D-2 Receptor

Full text
Silva, Rafaela R. [1] ; Parreiras-e-Silva, Lucas T. [2] ; Pompeu, Thais E. T. [1] ; Duarte, Diego A. [2] ; Fraga, Carlos A. M. [3] ; Barreiro, Eliezer J. [3] ; Menegatti, Ricardo [4] ; Costa-Neto, Claudio M. [2] ; Noel, Francois [1]
Total Authors: 9
[1] Univ Fed Rio de Janeiro, Inst Biomed Sci, Lab Biochem & Mol Pharmacol, Rio De Janeiro - Brazil
[2] Univ Sao Paulo, Ribeirao Preto Med Sch, Dept Biochem & Immunol, Lab Struct & Funct 7 Transmembrane Receptors 7TMR, Ribeirao Preto - Brazil
[3] Univ Fed Rio de Janeiro, Inst Biomed Sci, Lab Evaluat & Synth Bioact Subst LASSBio, Rio De Janeiro - Brazil
[4] Univ Fed Goias, Sch Pharm, Lab Quim Farmaceut Med, Goiania, Go - Brazil
Total Affiliations: 4
Document type: Journal article
Web of Science Citations: 0

LASSBio-579, an N-phenylpiperazine antipsychotic lead compound, has been previously reported as a D-2 receptor (D2R) ligand with antipsychotic-like activities in rodent models of schizophrenia. In order to better understand the molecular mechanism of action of LASSBio-579 and of its main metabolite, LQFM 037, we decided to address the hypothesis of functional selectivity at the D2R. HEK-293T cells transiently coexpressing the human long isoform of D-2 receptor (D2LR) and bioluminescence resonance energy transfer (BRET)-based biosensors were used. The antagonist activity was evaluated using different concentrations of the compounds in the presence of a submaximal concentration of dopamine (DA), after 5 and 20 min. For both signaling pathways, haloperidol, clozapine, and our compounds act as DA antagonists in a concentration-dependent manner, with haloperidol being by far the most potent, consistent with its nanomolar D2R affinity measured in binding assays. In our experimental conditions, only haloperidol presented a robust functional selectivity, being four-to fivefold more efficient for inhibiting translocation of beta-arrestin-2 (beta-arr2) than for antagonizing Gi activation. Present data are the first report on the effects of LASSBio-579 and LQFM 037 on the beta-arr2 signaling pathway and further illustrate that the functional activity could vary depending on the assay conditions and approaches used. (AU)

FAPESP's process: 12/20148-0 - Development of new ligands/drugs with selective agonism action (biased agonism) for receptors of the renin-angiotensin and kallikrein-kinin systems: new properties and new biotechnological applications
Grantee:Claudio Miguel da Costa Neto
Support type: Research Projects - Thematic Grants