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Article

Development of Pleiotropic TrkB and 5-HT4 Receptor Ligands as Neuroprotective Agents

by
Mirjana Antonijevic
1,†,
Despoina Charou
2,3,†,
Audrey Davis
1,
Thomas Curel
4,
Maria Valcarcel
5,
Isbaal Ramos
5,
Patricia Villacé
5,
Sylvie Claeysen
4,
Patrick Dallemagne
1,
Achille Gravanis
2,3,
Ioannis Charalampopoulos
2,3 and
Christophe Rochais
1,*
1
Normandie University, Unicaen, Centre d’Etudes et de Recherche sur le Médicament de Normandie (CERMN), 14000 Caen, France
2
Department of Pharmacology, Medical School, University of Crete, 70013 Heraklion, Greece
3
Institute of Molecular Biology & Biotechnology, Foundation of Research & Technology-Hellas, 70013 Heraklion, Greece
4
IGF, Univ Montpellier, CNRS, INSERM, 34000 Montpellier, France
5
Innoprot S.L, 48160 Derio, Spain
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Molecules 2024, 29(2), 515; https://doi.org/10.3390/molecules29020515
Submission received: 14 December 2023 / Revised: 12 January 2024 / Accepted: 16 January 2024 / Published: 19 January 2024
(This article belongs to the Special Issue Breakthroughs and Challenges in Medicinal Chemistry: New Targets and Mechanisms, New Drugs, New Hopes)
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Abstract

One common event that is the most detrimental in neurodegenerative disorders, even though they have a complex pathogenesis, is the increased rate of neuronal death. Endogenous neurotrophins consist of the major neuroprotective factors, while brain-derived neurotrophic factor (BDNF) and its high-affinity tyrosine kinase receptor TrkB are described in a number of studies for their important neuronal effects. Normal function of this receptor is crucial for neuronal survival, differentiation, and synaptic function. However, studies have shown that besides direct activation, the TrkB receptor can be transactivated via GPCRs. It has been proven that activation of the 5-HT4 receptor and transactivation of the TrkB receptor have a positive influence on neuronal differentiation (total dendritic length, number of primary dendrites, and branching index). Because of that and based on the main structural characteristics of LM22A-4, a known activator of the TrkB receptor, and RS67333, a partial 5-HT4 receptor agonist, we have designed and synthesized a small data set of novel compounds with potential dual activities in order to not only prevent neuronal death, but also to induce neuronal differentiation in neurodegenerative disorders.
Keywords: neurodegeneration; TrkB receptor; 5-HT4 receptor; neuronal survival; neurite differentiation neurodegeneration; TrkB receptor; 5-HT4 receptor; neuronal survival; neurite differentiation
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MDPI and ACS Style

Antonijevic, M.; Charou, D.; Davis, A.; Curel, T.; Valcarcel, M.; Ramos, I.; Villacé, P.; Claeysen, S.; Dallemagne, P.; Gravanis, A.; et al. Development of Pleiotropic TrkB and 5-HT4 Receptor Ligands as Neuroprotective Agents. Molecules 2024, 29, 515. https://doi.org/10.3390/molecules29020515

AMA Style

Antonijevic M, Charou D, Davis A, Curel T, Valcarcel M, Ramos I, Villacé P, Claeysen S, Dallemagne P, Gravanis A, et al. Development of Pleiotropic TrkB and 5-HT4 Receptor Ligands as Neuroprotective Agents. Molecules. 2024; 29(2):515. https://doi.org/10.3390/molecules29020515

Chicago/Turabian Style

Antonijevic, Mirjana, Despoina Charou, Audrey Davis, Thomas Curel, Maria Valcarcel, Isbaal Ramos, Patricia Villacé, Sylvie Claeysen, Patrick Dallemagne, Achille Gravanis, and et al. 2024. "Development of Pleiotropic TrkB and 5-HT4 Receptor Ligands as Neuroprotective Agents" Molecules 29, no. 2: 515. https://doi.org/10.3390/molecules29020515

APA Style

Antonijevic, M., Charou, D., Davis, A., Curel, T., Valcarcel, M., Ramos, I., Villacé, P., Claeysen, S., Dallemagne, P., Gravanis, A., Charalampopoulos, I., & Rochais, C. (2024). Development of Pleiotropic TrkB and 5-HT4 Receptor Ligands as Neuroprotective Agents. Molecules, 29(2), 515. https://doi.org/10.3390/molecules29020515

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