2. Academic Validation
  3. 5-HT6 receptor neutral antagonists protect astrocytes: A lesson from 2-phenylpyrrole derivatives

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

  • Eur J Med Chem. 2024 Sep 5:275:116615. doi: 10.1016/j.ejmech.2024.116615.
Marcin Drop 1,  Paulina Koczurkiewicz-Adamczyk 2,  Ophélie Bento 3,  Wojciech Pietruś 4,  Grzegorz Satała 4,  Klaudia Blicharz-Futera 2,  Vittorio Canale 2,  Katarzyna Grychowska 2,  Xavier Bantreil 5,  Elżbieta Pękala 2,  Rafał Kurczab 4,  Andrzej J Bojarski 4,  Severine Chaumont-Dubel 6,  Philippe Marin 6,  Frédéric Lamaty 7,  Paweł Zajdel 8
Affiliations

Affiliations

  • 1 Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Str., 30-688, Kraków, Poland; IBMM, Université de Montpellier, CNRS, ENSCM, 34095, Montpellier, France.
  • 2 Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Str., 30-688, Kraków, Poland.
  • 3 IBMM, Université de Montpellier, CNRS, ENSCM, 34095, Montpellier, France; Institut de Génomique Fonctionelle, Université de Montpellier, CNRS INSERM, 34094, Montpellier, France.
  • 4 Maj Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Str., 31-343, Kraków, Poland.
  • 5 IBMM, Université de Montpellier, CNRS, ENSCM, 34095, Montpellier, France; Institut Universitaire de France (IUF), France.
  • 6 Institut de Génomique Fonctionelle, Université de Montpellier, CNRS INSERM, 34094, Montpellier, France.
  • 7 IBMM, Université de Montpellier, CNRS, ENSCM, 34095, Montpellier, France.
  • 8 Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Str., 30-688, Kraków, Poland. Electronic address: pawel.zajdel@uj.edu.pl.
PMID: 38936149 DOI: 10.1016/j.ejmech.2024.116615
Abstract

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.

Keywords

2-phenylpyrrole; 5-HT(6) receptor; Constitutive activity; Cytoprotection; Human astrocytes; Inverse agonism; Neutral antagonism.

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