Promethazine inhibits NMDA-induced currents – New pharmacological aspects of an old drug

Background and purposeThe phenothiazine derivative promethazine was first introduced into clinical practice as an antiallergic drug owing to its H1-receptor antagonizing properties. Nowadays, promethazine is primarily used as a sedative and/or as an antiemetic. The spectrum of clinically relevant effects is mediated by different molecular targets. Since glutamate is the predominant excitatory transmitter in the vertebrate brain and involved in alertness control, pain processing, and neurotoxicity we tested the hypothesis that promethazine interacts with excitatory ionotropic glutamate receptors.Experimental approachElectrophysiological experiments were performed by means of the patch-clamp technique at glutamate receptors heterologously expressed in human TsA cells.Key resultsPromethazine 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 μM 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 (zδ = 0.44 ± 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.Conclusion and implicationsPromethazine 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.

► Promethazine selectively inhibits NMDA receptors.
► There is no competition of the drug with the glutamate- or the glycine binding site.
►  Promethazine seems to interact with the channel pore more externally than Mg2+.
► Results provide a possible explanation for the analgesic effect of promethazine.