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
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 s...
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MDPI AG
2021-07-01
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| author | Piotr Pankiewicz 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 Mikołaj Matłoka |
| author_facet | Piotr Pankiewicz 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 Mikołaj Matłoka |
| author_sort | Piotr Pankiewicz |
| collection | DOAJ |
| description | 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 K<sub>d</sub> = 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. |
| first_indexed | 2024-03-10T08:29:27Z |
| format | Article |
| id | doaj.art-9bb1dda14c4f450caccc553dfbb7d53e |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-10T08:29:27Z |
| publishDate | 2021-07-01 |
| publisher | MDPI AG |
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| series | Pharmaceuticals |
| spelling | doaj.art-9bb1dda14c4f450caccc553dfbb7d53e2023-11-22T09:10:28ZengMDPI AGPharmaceuticals1424-82472021-07-0114870410.3390/ph14080704Do 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 AgonistsPiotr Pankiewicz0Marcin Szybiński1Katarzyna Kisielewska2Filip Gołębiowski3Patryk Krzemiński4Izabela Rutkowska-Włodarczyk5Rafał Moszczyński-Pętkowski6Lidia Gurba-Bryśkiewicz7Monika Delis8Krzysztof Mulewski9Damian Smuga10Jakub Dominowski11Artur Janusz12Michał Górka13Krzysztof Abramski14Agnieszka Napiórkowska15Marcin Nowotny16Krzysztof Dubiel17Katarzyna Kalita18Maciej Wieczorek19Jerzy Pieczykolan20Mikołaj Matłoka21Celon Pharma Innovative Drugs Research & Development Department, Celon Pharma S.A., 05-152 Kazun Nowy, PolandCelon Pharma Innovative Drugs Research & Development Department, Celon Pharma S.A., 05-152 Kazun Nowy, PolandCelon Pharma Innovative Drugs Research & Development Department, Celon Pharma S.A., 05-152 Kazun Nowy, PolandCelon Pharma Innovative Drugs Research & Development Department, Celon Pharma S.A., 05-152 Kazun Nowy, PolandCelon Pharma Innovative Drugs Research & Development Department, Celon Pharma S.A., 05-152 Kazun Nowy, PolandCelon Pharma Innovative Drugs Research & Development Department, Celon Pharma S.A., 05-152 Kazun Nowy, PolandCelon Pharma Innovative Drugs Research & Development Department, Celon Pharma S.A., 05-152 Kazun Nowy, PolandCelon Pharma Innovative Drugs Research & Development Department, Celon Pharma S.A., 05-152 Kazun Nowy, PolandCelon Pharma Innovative Drugs Research & Development Department, Celon Pharma S.A., 05-152 Kazun Nowy, PolandCelon Pharma Innovative Drugs Research & Development Department, Celon Pharma S.A., 05-152 Kazun Nowy, PolandCelon Pharma Innovative Drugs Research & Development Department, Celon Pharma S.A., 05-152 Kazun Nowy, PolandCelon Pharma Innovative Drugs Research & Development Department, Celon Pharma S.A., 05-152 Kazun Nowy, PolandCelon Pharma Innovative Drugs Research & Development Department, Celon Pharma S.A., 05-152 Kazun Nowy, PolandCelon Pharma Innovative Drugs Research & Development Department, Celon Pharma S.A., 05-152 Kazun Nowy, PolandCelon Pharma Innovative Drugs Research & Development Department, Celon Pharma S.A., 05-152 Kazun Nowy, PolandStructural Biology Center, International Institute of Molecular and Cell Biology, 02-109 Warsaw, PolandStructural Biology Center, International Institute of Molecular and Cell Biology, 02-109 Warsaw, PolandCelon Pharma Innovative Drugs Research & Development Department, Celon Pharma S.A., 05-152 Kazun Nowy, PolandLaboratory of Neurobiology, Nencki-EMBL Partnership for Neural Plasticity and Brain Disorders—BRAINCITY, Nencki Institute of Experimental Biology PAS, 02-093 Warsaw, PolandCelon Pharma Innovative Drugs Research & Development Department, Celon Pharma S.A., 05-152 Kazun Nowy, PolandCelon Pharma Innovative Drugs Research & Development Department, Celon Pharma S.A., 05-152 Kazun Nowy, PolandCelon Pharma Innovative Drugs Research & Development Department, Celon Pharma S.A., 05-152 Kazun Nowy, PolandTrkB 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 K<sub>d</sub> = 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.https://www.mdpi.com/1424-8247/14/8/704TrkB agonistdrug discovery7,8-DHF |
| spellingShingle | Piotr Pankiewicz 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 Mikołaj Matłoka 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 TrkB agonist drug discovery 7,8-DHF |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | TrkB agonist drug discovery 7,8-DHF |
| url | https://www.mdpi.com/1424-8247/14/8/704 |
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