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

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.

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…The revolutionary potential of this possible discovery and the key role MD has played in it cannot be understated and already have been widely commented upon in the neuroscience community [1009][1010][1011][1012]; attempts have already been made to find small molecules which directly activate TRKB [1013] or positively stimulate BDNF signaling [1014]. We finally come to the last category of membrane-associated proteins, and arguably the most difficult to study of all: peripheral membrane proteins.…”

Production of brain-derived neurotrophic factor gates plasticity in developing visual cortex

“…These findings raise the possibility that the application of an artificial activator of the TrkB receptor might prove a powerful adjunct to physical or cognitive therapy for brain injuries and disorders (reviewed in refs. ( 49 – 51 ).…”

Pharmacological Enhancement of Extinction Retention in Non-stressed Adolescent Rats but Not Those Exposed to Chronic Corticosterone

“…Whilst this adjunct was initially proposed to be a tropomyosin receptor kinase B (TrkB) agonist ( Jang et al, 2010 ; Liu et al, 2014 ), and there is evidence that 7,8-DHF (at 5 mg/kg, the same dose as used in the current study) upregulates phosphorylation of TrkB in the amygdala 1 and 2 h after systemic delivery in adult mice ( Andero et al, 2011 ), the pharmacology of 7,8-DHF is more complex than initially assumed. Several alternative targets than TrkB receptors may mediate its neurobehavioral actions in vivo , including activation of adenosine receptors ( Pankiewicz et al, 2021 ). In addition, as we administered the drug systemically it is not possible to deduce whether 7,8-DHF acted centrally to facilitate extinction retention in non-stressed adolescent rats.…”