Promethazine inhibits NMDA-induced currents - new pharmacological aspects of an old drug.
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Adolph O, Koster S, Georgieff M, Georgieff EM, Moulig W, Fohr KJ
Promethazine inhibits NMDA-induced currents - new pharmacological aspects of an old drug.
Neuropharmacology. 2012 Aug;63(2):280-91. doi: 10.1016/j.neuropharm.2012.03.006. Epub 2012 Apr 7.
- PubMed ID
- 22507664 [ View in PubMed]
- Abstract
BACKGROUND AND PURPOSE: The 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 APPROACH: Electrophysiological experiments were performed by means of the patch-clamp technique at glutamate receptors heterologously expressed in human TsA cells. KEY RESULTS: 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 muM 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 (zdelta = 0.44 +/- 0.04 according to the Woodhull-model). In line with the latter finding, promethazine did not interact with the Mg(2+) 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 Mg(2+) binding site. CONCLUSION AND IMPLICATIONS: 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.
DrugBank Data that Cites this Article
- Drugs
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Propiomazine 5-hydroxytryptamine receptor 2A Protein Humans UnknownAntagonistDetails Propiomazine 5-hydroxytryptamine receptor 2C Protein Humans UnknownAntagonistDetails Propiomazine Dopamine D2 receptor Protein Humans UnknownAntagonistDetails