Evaluation of CBD effects on the molecular and behavioral changes induced by repea...
| Full text | |
| 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]
Total Authors: 9
|
| 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
Total Affiliations: 4
|
| 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 type: | Research Projects - Thematic Grants |