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Do Small Molecules Activate the TrkB Receptor in the Same Manner as BDNF? Limitations of Published TrkB Low Molecular Agonists and Screening for Novel TrkB Orthosteric Agonists

1
Celon Pharma Innovative Drugs Research & Development Department, Celon Pharma S.A., 05-152 Kazun Nowy, Poland
2
Postgraduate School of Molecular Medicine, Medical University of Warsaw, 02-091 Warsaw, Poland
3
Structural Biology Center, International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland
4
Laboratory of Protein Structure, International Institute of Molecular and Cell Biology, 02-109 Warsaw, Poland
5
Laboratory of Neurobiology, Nencki-EMBL Partnership for Neural Plasticity and Brain Disorders—BRAINCITY, Nencki Institute of Experimental Biology PAS, 02-093 Warsaw, Poland
*
Author to whom correspondence should be addressed.
Pharmaceuticals 2021, 14(8), 704; https://doi.org/10.3390/ph14080704
Received: 18 June 2021 / Revised: 14 July 2021 / Accepted: 15 July 2021 / Published: 21 July 2021
(This article belongs to the Section Pharmacology)
TrkB is a tyrosine kinase receptor that is activated upon binding to brain-derived neurotrophic factor (BDNF). To date, the search for low-molecular-weight molecules mimicking BDNF’s action has been unsuccessful. Several molecules exerting antidepressive effects in vivo, such as 7,8-DHF, have been suggested to be TrkB agonists. However, more recent publications question this hypothesis. In this study, we developed a set of experimental procedures including the evaluation of direct interactions, dimerization, downstream signaling, and cytoprotection in parallel with physicochemical and ADME methods to verify the pharmacology of 7,8-DHF and other potential reference compounds, and perform screening for novel TrkB agonists. 7,8 DHF bound to TrkB with Kd = 1.3 μM; however, we were not able to observe any other activity against the TrkB receptor in SN56 T48 and differentiated SH-SY5Y cell lines. Moreover, the pharmacokinetic and pharmacodynamic effects of 7,8-DHF at doses of 1 and 50 mg/kg were examined in mice after i.v and oral administration, respectively. The poor pharmacokinetic properties and lack of observed activation of TrkB-dependent signaling in the brain confirmed that 7,8-DHF is not a relevant tool for studying TrkB activation in vivo. The binding profile for 133 molecular targets revealed a significant lack of selectivity of 7,8-DHF, suggesting a distinct functional profile independent of interaction with TrkB. Additionally, a compound library was screened in search of novel low-molecular-weight orthosteric TrkB agonists; however, we were not able to identify reliable drug candidates. Our results suggest that published reference compounds including 7,8-DHF do not activate TrkB, consistent with canonical dogma, which indicates that the reported pharmacological activity of these compounds should be interpreted carefully in a broad functional context. View Full-Text
Keywords: TrkB agonist; drug discovery; 7,8-DHF TrkB agonist; drug discovery; 7,8-DHF
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MDPI and ACS Style

Pankiewicz, P.; Szybiński, M.; Kisielewska, K.; Gołębiowski, F.; Krzemiński, P.; Rutkowska-Włodarczyk, I.; Moszczyński-Pętkowski, R.; Gurba-Bryśkiewicz, L.; Delis, M.; Mulewski, K.; Smuga, D.; Dominowski, J.; Janusz, A.; Górka, M.; Abramski, K.; Napiórkowska, A.; Nowotny, M.; Dubiel, K.; Kalita, K.; Wieczorek, M.; Pieczykolan, J.; Matłoka, M. Do Small Molecules Activate the TrkB Receptor in the Same Manner as BDNF? Limitations of Published TrkB Low Molecular Agonists and Screening for Novel TrkB Orthosteric Agonists. Pharmaceuticals 2021, 14, 704. https://doi.org/10.3390/ph14080704

AMA Style

Pankiewicz P, Szybiński M, Kisielewska K, Gołębiowski F, Krzemiński P, Rutkowska-Włodarczyk I, Moszczyński-Pętkowski R, Gurba-Bryśkiewicz L, Delis M, Mulewski K, Smuga D, Dominowski J, Janusz A, Górka M, Abramski K, Napiórkowska A, Nowotny M, Dubiel K, Kalita K, Wieczorek M, Pieczykolan J, Matłoka M. Do Small Molecules Activate the TrkB Receptor in the Same Manner as BDNF? Limitations of Published TrkB Low Molecular Agonists and Screening for Novel TrkB Orthosteric Agonists. Pharmaceuticals. 2021; 14(8):704. https://doi.org/10.3390/ph14080704

Chicago/Turabian Style

Pankiewicz, Piotr, Marcin Szybiński, Katarzyna Kisielewska, Filip Gołębiowski, Patryk Krzemiński, Izabela Rutkowska-Włodarczyk, Rafał Moszczyński-Pętkowski, Lidia Gurba-Bryśkiewicz, Monika Delis, Krzysztof Mulewski, Damian Smuga, Jakub Dominowski, Artur Janusz, Michał Górka, Krzysztof Abramski, Agnieszka Napiórkowska, Marcin Nowotny, Krzysztof Dubiel, Katarzyna Kalita, Maciej Wieczorek, Jerzy Pieczykolan, and Mikołaj Matłoka. 2021. "Do Small Molecules Activate the TrkB Receptor in the Same Manner as BDNF? Limitations of Published TrkB Low Molecular Agonists and Screening for Novel TrkB Orthosteric Agonists" Pharmaceuticals 14, no. 8: 704. https://doi.org/10.3390/ph14080704

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