Electrophysiological experiments were performed by means of the patch-clamp technique at glutamate receptors heterologously expressed in human TsA cells.
Promethazine selectively inhibited NMDA receptors whereas AMPA- and kainate receptors were hardly affected. Inhibition of NMDA-induced membrane currents occurred in a reversible manner with a half-maximal effect at around 20聽渭M promethazine. The inhibition occurred in a non-competitive manner as it did neither vary with the glutamate nor the glycine concentration. Analysis of the underlying mechanism revealed only a weak dependency on receptor usage, pH value (pH 6.8-7.8), and membrane potential (z未聽=聽0.44聽卤聽0.04 according to the Woodhull-model). In line with the latter finding, promethazine did not interact with the Mg2+ binding site. However, the displacement of promethazine by 9-aminoacridine indicates that promethazine may interact with the channel pore more externally in relation to the Mg2+ binding site.
Promethazine inhibits NMDA-mediated membrane currents in a reversible and concentration-dependent manner. The results presented here provide evidence that the NMDA receptor antagonism may contribute to clinically relevant effects of promethazine like sedation, analgesia or neuroprotection.