Introduction: Investigating the binding site of six novel curcumin-based diazepine compounds as a noncompetitive
antagonist on ionotropic, AMPA-type glutamate receptors, including homomeric and heteromeric
subunits. These receptors play a pivotal role in neurodegenerative diseases such as Alzheimer’s and epilepsy due
to excitotoxicity. Furthermore, it appears that AMPAR signaling plays a significant role in disease development
outside the nervous system, as a potential relationship between AMPAR activation and cancer development may
exist.
Objectives: Study the biophysical gating effects of the curcumin-based diazepine on AMPAR variants and identify
CBD binding sites on AMPARs with the hopes of discovering more potent drug candidates with less undesirable
side effects.
Methods: Our current study uses patch-clamp electrophysiology technology to estimate whole-cell amplitudes
changes when exposing HEK293T cells expressing AMPAR subunits to different curcumin-based diazepines.
Results: The non-competitive antagonist curcumin-based compounds successfully reduced AMPAR activation
currents and increased the rate of desensitization and deactivation. CBD-4 and CBD-5 show the most significant
impact on AMPARs, reducing the current by 7-fold. The results contrast with those obtained by the halogenated
benzodiazepine-fused curcumins reported previously and lake pyrimidine and pyrazine moieties. This indicates
that the N’s presence in the effused rings plays a significant role in binding to receptors. CBD-4 showed the
highest effect on GluA2 subunits in receptors, while CBD-5 most dramatically impacting GluA1 homomeric receptors,
demonstrating that the compounds are more selective towards AMPA-type glutamate receptors. The
compounds also showed significant cytotoxic activities against breast cancer cell line (MCF-7), with CBD-4
having the most significant impact.
Conclusion: Curcumin-based compounds (i.e., CBD-4 and CBD-5) yield significant neurodegenerative drug potential,
and it creates a novel structure with significant activities in reducing AMPAR excitation compared to
traditional benzodiazepine analogs, yet their binding mechanisms are still not fully understood. Moreover,
AMPARs appear to have a potential influence on cancer development, and the curcumin-based compounds might
provide insight into the nature of this relationship.