5-HT 6 receptor neutral antagonists protect astrocytes: A lesson from 2-phenylpyrrole derivatives

• Published in: European journal of medicinal chemistry Vol. 275; p. 116615
• Main Authors: Drop, Marcin, Koczurkiewicz-Adamczyk, Paulina, Bento, Ophélie, Pietruś, Wojciech, Satała, Grzegorz, Blicharz-Futera, Klaudia, Canale, Vittorio, Grychowska, Katarzyna, Bantreil, Xavier, Pękala, Elżbieta, Kurczab, Rafał, Bojarski, Andrzej J, Chaumont-Dubel, Severine, Marin, Philippe, Lamaty, Frédéric, Zajdel, Paweł
• Format: Journal Article
• Language: English
• Published: France 05.09.2024
• Subjects: Animals; Astrocytes - drug effects; Astrocytes - metabolism; Dose-Response Relationship, Drug; Humans; Molecular Dynamics Simulation; Molecular Structure; Pyrroles - chemical synthesis; Pyrroles - chemistry; Pyrroles - pharmacology; Receptors, Serotonin - metabolism; Serotonin Antagonists - chemical synthesis; Serotonin Antagonists - chemistry; Serotonin Antagonists - pharmacology; Signal Transduction - drug effects; Structure-Activity Relationship; Neutral antagonism; Human astrocytes; 2-phenylpyrrole; Constitutive activity; 5-HT receptor; Inverse agonism; Cytoprotection
• ISSN: 1768-3254

The serotonin type 6 receptor (5-HT R) displays a strong constitutive activity, suggesting it participates largely in the physiological and pathological processes controlled by the receptor. The active states of 5-HT R engage particular signal transduction pathways that lead to different biological responses. In this study, we present the development of 5-HT R neutral antagonists at Gs signaling built upon the 2-phenylpyrrole scaffold. Using molecular dynamics simulations, we outline the relationship between the exposure of the basic center of the molecules and their ability to target the agonist-activated state of the receptor. Our study identifies compound 30 as a potent and selective neutral antagonist at 5-HT R-operated Gs signaling. Furthermore, we demonstrate the cytoprotective effects of 30 and structurally diverse 5-HT R neutral antagonists at Gs signaling in C8-D1A cells and human astrocytes exposed to rotenone. This effect is not observed for 5-HT R agonists or inverse agonists. In light of these findings, we propose compound 30 as a valuable molecular probe to study the biological effects associated with the agonist-activated state of 5-HT R and provide insight into the glioprotective properties of 5-HT R neutral antagonists at Gs signaling.