A quest for the stereo-electronic requirements for selective agonism for the neurotrophin receptors TrkA and TrkB in 17-spirocyclic-dehydroepiandrosterone derivatives

Frontiers in Molecular Neuroscience

Molecular Neuroscience

Theodora Katsila¹  Kyriakos C. Prousis¹  Daniele Narducci¹  Theodora Calogeropoulou¹  Vivi Bafiti¹  Maria Zervou¹  Achille Gravanis²  Ioanna Zota²  Thanasis Rogdakis²  Ioannis Charalampopoulos²  Despoina Charou² 

[1] Institute of Chemical Biology, National Hellenic Research Foundation, Athens, Greece;Institute of Molecular Biology and Biotechnology, Foundation for Research and Technology Hellas, Heraklion, Greece;Department of Pharmacology, Medical School, University of Crete, Heraklion, Greece;

关键词: neurotrophin mimetics;    TrkA;    TrkB;    receptor agonists;    signaling;    neuroprotection;    neurodegeneration;    DHEA derivatives;   

DOI  :  10.3389/fnmol.2023.1244133

 received in 2023-06-21, accepted in 2023-08-31,  发布年份 2023

来源: Frontiers

【 摘 要 】

IntroductionThe neurotrophin system plays a pivotal role in the development, morphology, and survival of the nervous system, and its dysregulation has been manifested in numerous neurodegenerative and neuroinflammatory diseases. Neurotrophins NGF and BDNF are major growth factors that prevent neuronal death and synaptic loss through binding with high affinity to their specific tropomyosin-related kinase receptors namely, TrkA and TrkB, respectively. The poor pharmacokinetic properties prohibit the use of neurotrophins as therapeutic agents. Our group has previously synthesized BNN27, a prototype small molecule based on dehydroepiandrosterone, mimicking NGF through the activation of the TrkA receptor.MethodsTo obtain a better understanding of the stereo-electronic requirements for selective activation of TrkA and TrkB receptors, 27 new dehydroepiandrosterone derivatives bearing a C17-spiro-dihydropyran or cyclobutyl moiety were synthesized. The new compounds were evaluated for their ability (a) to selectively activate the TrkA receptor and its downstream signaling kinases Akt and Erk1/2 in PC12 cells, protecting these cells from serum deprivation-induced cell death, and (b) to induce phosphorylation of TrkB and to promote cell survival under serum deprivation conditions in NIH3T3 cells stable transfected with the TrkB receptor and primary cortical astrocytes. In addition the metabolic stability and CYP-mediated reaction was assessed.ResultsAmong the novel derivatives, six were able to selectively protect PC12 cells through interaction with the TrkA receptor and five more to selectively protect TrkB-expressing cells via interaction with the TrkB receptor. In particular, compound ENT-A025 strongly induces TrkA and Erk1/2 phosphorylation, comparable to NGF, and can protect PC12 cells against serum deprivation-induced cell death. Furthermore, ENT-A065, ENT-A066, ENT-A068, ENT-A069, and ENT-A070 showed promising pro-survival effects in the PC12 cell line. Concerning TrkB agonists, ENT-A009 and ENT-A055 were able to induce phosphorylation of TrkB and reduce cell death levels in NIH3T3-TrkB cells. In addition, ENT-A076, ENT-A087, and ENT-A088 possessed antiapoptotic activity in NIH-3T3-TrkB cells exclusively mediated through the TrkB receptor. The metabolic stability and CYP-mediated reaction phenotyping of the potent analogs did not reveal any major liabilities.DiscussionWe have identified small molecule selective agonists of TrkA and TrkB receptors as promising lead neurotrophin mimetics for the development of potential therapeutics against neurodegenerative conditions.

【 授权许可】

Unknown   
Copyright © 2023 Narducci, Charou, Rogdakis, Zota, Bafiti, Zervou, Katsila, Gravanis, Prousis, Charalampopoulos and Calogeropoulou.