Mechanisms of NMDA receptor inhibition by chlorhexidine and alexidine

NMDA receptors are inhibited by many cationic compounds including amines, amidines and guanidines. In this work we have for the first time tested two bisbiguanide compounds - an antiseptic and disinfectant chlorhexidine and antimicrobial agent alexidine - for their activity against NMDA receptors. Experiments were performed on native NMDA receptors of isolated rat CA1 hippocampal pyramidal neurons using whole-cell patch-clamp method. Chlorhexidine and alexidine inhibited these native NMDA receptors with the IC₅₀ values of 81 ± 5 nM and 144 ± 13 nM, respectively, at -80 mV holding voltage. They were more than an order of magnitude more active than previously studied monobiguanide compounds proguanil, cycloguanil and phenformin with the IC₅₀ values of 3-13 μM in the same experimental conditions. The inhibition by chlorhexidine and alexidine was reversible, not competitive and practically voltage-independent, suggesting allosteric effect as the main molecular mechanism of their action on NMDA receptors. This work expands the existing understanding of the molecular mechanisms of NMDA Receptor inhibition by biguanide compounds, which is useful for the search and development of new drugs for which these receptors would be the main target.

Alexidine; Bisbiguanides; Chlorhexidine; NMDA receptors; Patch clamp; Pharmacological modulation.