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

Author:

Antonijevic Mirjana1,Charou Despoina23,Davis Audrey1ORCID,Curel Thomas4ORCID,Valcarcel Maria5,Ramos Isbaal5ORCID,Villacé Patricia5,Claeysen Sylvie4ORCID,Dallemagne Patrick1ORCID,Gravanis Achille23ORCID,Charalampopoulos Ioannis23ORCID,Rochais Christophe1ORCID

Affiliation:

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

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.

Funder

European Union’s Horizon 2020 research and innovation program under the Marie Skłodowska-Curie grant

Publisher

MDPI AG

Subject

Chemistry (miscellaneous),Analytical Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Molecular Medicine,Drug Discovery,Pharmaceutical Science

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