Binding and Activation of Serotonergic G-Protein Coupled Receptors by the Multimodal Antidepressant Vortioxetine.
ACS Chem Neurosci
; 13(8): 1129-1142, 2022 04 20.
Article
em En
| MEDLINE
| ID: mdl-35348335
ABSTRACT
G-protein coupled receptors (GPCRs) are important pharmacological targets. Despite substantial progress, important questions still remain concerning the details of activation how can a ligand act as an agonist in one receptor but as an antagonist in a homologous receptor, and how can agonists activate a receptor despite lacking polar functional groups able to interact with helix 5 as is the case for the related adrenergic receptors? Studying vortioxetine (VXT), an important multimodal antidepressant drug, may elucidate both questions. Herein, we present a thorough in silico analysis of VXT binding to 5-HT1A, 5-HT1B, and 5-HT7 receptors and compare it with available experimental data. We are able to rationalize the differential mode of action of VXT at different receptors, but also, in the case of the 5-HT1A receptor, we observe the initial steps of activation that inform about an activation mechanism that does not involve polar interaction with helix 5. The results extend our current understanding of agonist and antagonist action at aminergic GPCRs.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Piperazinas
/
Serotonina
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article