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

Author(s)

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]

Affiliation

^[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

• Document type: Journal article
• Source: FRONTIERS IN PHARMACOLOGY; v. 10, JUN 4 2019.
• Web of Science Citations: 0

Abstract

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 Opportunities: Research Projects - Thematic Grants