Introduction

Investigating the binding site of six novel curcumin-based diazepine compounds as a non-competitive 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.

Title

Bioorganic Chemistry

Publisher

Academic Press

Publisher Country

United States of America

Indexing

Thomson Reuters

Impact Factor

5.275

Publication Type

Both (Printed and Online)

Volume

116

Year

2021

Pages

105406