2. Academic Validation
  3. Design, synthesis and biological characterization of novel activators of the TrkB neurotrophin receptor

Design, synthesis and biological characterization of novel activators of the TrkB neurotrophin receptor

  • Eur J Med Chem. 2023 Feb 15;248:115111. doi: 10.1016/j.ejmech.2023.115111.
Mirjana Antonijevic 1,  Despoina Charou 2,  Isbaal Ramos 3,  Maria Valcarcel 3,  Achille Gravanis 2,  Patricia Villace 3,  Noelle Callizot 4,  Marc Since 1,  Patrick Dallemagne 1,  Ioannis Charalampopoulos 2,  Christophe Rochais 5
Affiliations

Affiliations

  • 1 Normandie Univ., UNICAEN, CERMN, 14000, Caen, France.
  • 2 Department of Pharmacology, Medical School, University of Crete, Heraklion, Greece; Institute of Molecular Biology & Biotechnology, Foundation for Research & Technology-Hellas (IMBB-FORTH), Heraklion, Greece.
  • 3 Innoprot S.L, Derio, Bizkaia, Spain.
  • 4 Neurosys, Gardanne, France.
  • 5 Normandie Univ., UNICAEN, CERMN, 14000, Caen, France. Electronic address: [email protected].
PMID: 36645981 DOI: 10.1016/j.ejmech.2023.115111
Abstract

Numerous studies have been published about the implication of the neurotrophin brain-derived neurotrophic factor (BDNF) and its receptor TrkB in the pathogenesis of several neurodegenerative conditions such as Alzheimer's disease, Parkinson's disease, Multiple Sclerosis and motor neuron disease. BDNF activates the TrkB receptor with high potency and specificity, promoting neuronal survival, differentiation and synaptic plasticity. Based on the main structural characteristics of LM22A-4, a previously published small molecule that acts as activator of the TrkB receptor, we have designed and synthesized a small data set of compounds. The lead idea for the design of the new compounds was to modify the third position of the LM22A-4, by introducing different substitutions in order to obtain compounds which will have not only better physicochemical properties but selective activity as well. ADME and toxicity profiles of molecules have been evaluated as well as their biological properties through the TrkB receptor and affinity to promote neurite differentiation.

Keywords

Activators; Neurite differentiation; Neurotrophins; Physicochemical properties; TrkB receptor.

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