5-HT6 receptor neutral antagonists protect astrocytes: A lesson from 2-phenylpyrrole derivatives

• Published in: European journal of medicinal chemistry 2024-09, Vol.275, p.116615, Article 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: Article
• Language: English
• Subjects: 2-phenylpyrrole; 5-HT6 receptor; Chemical Sciences; Constitutive activity; Cytoprotection; Human astrocytes; Inverse agonism; Life Sciences; Medicinal Chemistry; Neurobiology; Neurons and Cognition; Neutral antagonism; Pharmaceutical sciences; Pharmacology
• ISSN: 0223-5234; 1768-3254; 1768-3254
• DOI: 10.1016/j.ejmech.2024.116615

The serotonin type 6 receptor (5-HT6R) displays a strong constitutive activity, suggesting it participates largely in the physiological and pathological processes controlled by the receptor. The active states of 5-HT6R engage particular signal transduction pathways that lead to different biological responses. In this study, we present the development of 5-HT6R 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-HT6R-operated Gs signaling. Furthermore, we demonstrate the cytoprotective effects of 30 and structurally diverse 5-HT6R neutral antagonists at Gs signaling in C8-D1A cells and human astrocytes exposed to rotenone. This effect is not observed for 5-HT6R 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-HT6R and provide insight into the glioprotective properties of 5-HT6R neutral antagonists at Gs signaling. [Display omitted] •A novel framework for 5-HT6R ligands derived from 2-phenylpyrrole.•Exposure of the basic center is cricial to target different active states of 5-HT6R.•Compound 30 behaves as neutral antagonist at 5-HT6R-operated Gs signaling.•5-HT6R neutral antagonists show cytoprotective effect in C8-D1A and human astrocytes.•Agonists and inverse agonists of 5-HT6R produce no cytoprotective effect.