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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

Pankiewicz, Piotr ; Szybiński, Marcin ; Kisielewska, Katarzyna ; [et al.]

MDPI AG ; 2021

In: Pharmaceuticals Vol. 14, No. 8 ( 2021-07-21), p. 704-

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In: Pharmaceuticals, MDPI AG, Vol. 14, No. 8 ( 2021-07-21), p. 704-

Abstract: 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.

Type of Medium: Online Resource

ISSN: 1424-8247

URL: Article

DOI: 10.3390/ph14080704

Language: English

Publisher: MDPI AG

Publication Date: 2021

detail.hit.zdb_id: 2193542-7

SSG: 15,3

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Evaluation of the hepatotoxicity of the novel GPR40 (FFAR1) agonist CPL207280 in the rat and monkey

Bazydlo-Guzenda, Katarzyna ; Buda, Pawel ; Mach, Mateusz ; [et al.]

Public Library of Science (PLoS) ; 2021

In: PLOS ONE Vol. 16, No. 9 ( 2021-9-23), p. e0257477-

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In: PLOS ONE, Public Library of Science (PLoS), Vol. 16, No. 9 ( 2021-9-23), p. e0257477-

Abstract: GPR40 (FFAR1) is a promising target for the managing type 2 diabetes (T2D). The most advanced GPR40 agonist TAK-875 exhibited satisfactory glucose-lowering effects in phase II and III studies. However, the phase III studies of TAK-875 revealed drug-induced liver injury (DILI). It is unknown whether DILI is a consequence of a specific GPR40 agonist or is an inherent feature of all GPR40 agonists. CPL207280 is a novel GPR40 agonist that improves diabetes in Zucker Diabetic Fatty (ZDF) rats, Goto Kakizaki (GK) rats and db/db mice. In this report, the DILI-related toxicity of CPL207280 was compared directly with that of TAK-875. In vitro studies evaluating hepatic biliary transporter inhibition, mitochondrial function, and metabolic profiling were performed in hepatocytes from different species. The long term toxicity of CPL207280 was studied in vivo in rats and monkeys. Activity of CPL207280 was one order of magnitude lesser than that of TAK-875 for the inhibition of bile acid transporters. CPL207280 had a negligible effect on the hepatic mitochondria. In contrast to TAK-875, which was metabolized through toxic glucuronidation, CPL207280 was metabolized mainly through oxidation. No deleterious hepatic effects were observed in chronically treated healthy and diabetic animals. The study presents promising data on the feasibility of creating a liver-safe GPR40 agonist. Additionally, it can be concluded that DILI is not a hallmark of GPR40 agonists; it is linked to the intrinsic properties of an individual agonist.

Type of Medium: Online Resource

ISSN: 1932-6203

URL: Article

DOI: 10.1371/journal.pone.0257477

DOI: 10.1371/journal.pone.0257477.g001

DOI: 10.1371/journal.pone.0257477.g002

DOI: 10.1371/journal.pone.0257477.g003

DOI: 10.1371/journal.pone.0257477.g004

DOI: 10.1371/journal.pone.0257477.g005

DOI: 10.1371/journal.pone.0257477.g006

DOI: 10.1371/journal.pone.0257477.g007

DOI: 10.1371/journal.pone.0257477.g008

DOI: 10.1371/journal.pone.0257477.g009

DOI: 10.1371/journal.pone.0257477.g010

DOI: 10.1371/journal.pone.0257477.g011

DOI: 10.1371/journal.pone.0257477.t001

DOI: 10.1371/journal.pone.0257477.t002

DOI: 10.1371/journal.pone.0257477.t003

DOI: 10.1371/journal.pone.0257477.t004

DOI: 10.1371/journal.pone.0257477.t005

DOI: 10.1371/journal.pone.0257477.s001

Language: English

Publisher: Public Library of Science (PLoS)

Publication Date: 2021

detail.hit.zdb_id: 2267670-3

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Preclinical characterization of CPL302-253, a selective inhibitor of PI3Kδ, as the candidate for the inhalatory treatment and prevention of Asthma

Gunerka, Paweł ; Gala, Kamila ; Banach, Martyna ; [et al.]

Public Library of Science (PLoS) ; 2020

In: PLOS ONE Vol. 15, No. 7 ( 2020-7-23), p. e0236159-

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In: PLOS ONE, Public Library of Science (PLoS), Vol. 15, No. 7 ( 2020-7-23), p. e0236159-

Type of Medium: Online Resource

ISSN: 1932-6203

URL: Article

DOI: 10.1371/journal.pone.0236159

DOI: 10.1371/journal.pone.0236159.g001

DOI: 10.1371/journal.pone.0236159.g002

DOI: 10.1371/journal.pone.0236159.g003

DOI: 10.1371/journal.pone.0236159.g004

DOI: 10.1371/journal.pone.0236159.g005

DOI: 10.1371/journal.pone.0236159.g006

DOI: 10.1371/journal.pone.0236159.g007

DOI: 10.1371/journal.pone.0236159.t001

DOI: 10.1371/journal.pone.0236159.t002

DOI: 10.1371/journal.pone.0236159.t003

DOI: 10.1371/journal.pone.0236159.t004

DOI: 10.1371/journal.pone.0236159.s001

Language: English

Publisher: Public Library of Science (PLoS)

Publication Date: 2020

detail.hit.zdb_id: 2267670-3

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