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The spectrum of action of flupirtine includes analgesic, muscle-relaxant and neuroprotective properties. The substance's mechanism of action has yet to be fully explained. Over the past few years, however, evidence has accumulated that flupirtine interacts with the glutamatergic N-Methyl-D-Aspartate (NMDA) receptor. Although it was not possible to demonstrate a direct effect on the NMDA receptor, all of the findings pointed to an indirect influence on the NMDA receptor in the sense of a functional NMDA antagonism. It was thus postulated that a site of action "up- or downstream" of the NMDA receptor is influenced. Such a site of action proved to be the G-protein-activated inwardly rectifying K+ channels (GIRK), the opening of which leads to a stabilization of the resting membrane potential of neuronal cells and thus causes an indirect inhibition of the NMDA receptor. At therapeutically relevant concentrations, flupirtine is a neuronal potassium channel opener. This mechanism may explain the spectrum of action of flupirtine. Selective neuronal potassium channel opening (SNEPCO) thus proves to be a new principle of action, making flupirtine the prototype of a new substance class with analgesic, muscle-relaxant and neuroprotective properties. The experimental basis for this working hypothesis and the resulting model concepts are presented from the perspective of a four-stage approach.

The spectrum of action of flupirtine includes analgesia, muscle relaxation and neuroprotection. N-methyl-D-aspartate (NMDA) receptor antagonism has been discussed as a possible mechanism of action of this compound with little direct evidence. The objective of the present study was to develop a plausible model to explain flupirtine's spectrum of action. A four-stage strategy was selected for this purpose: Firstly, the serum concentration of flupirtine under therapeutic conditions was determined on the basis of the current literature. The second stage involved assessing the known in-vitro effects in light of the therapeutic active concentration. Using whole cell patch clamp recordings from cultured rat superior colliculus neurones interactions between flupirtine and NMDA receptors were assessed. Only very high concentrations of flupirtine antagonized inward currents to NMDA (200 microM) at -70 mV with an lC50 against steady-state responses of 182.1+/-12.1 microM. The effects of flupirtine were voltage-independent and not associated with receptor desensitization making actions within the NMDA receptor channel or at the glycine modulatory site unlikely. NMDA receptor antagonism probably has little relevance for the clinical efficacy of flupirtine as the concentrations needed were far higher than those achieved in clinical practice. However, the activation of a G-protein-regulated inwardly rectifying K+ channel was identified as an interesting molecular target site of flupirtine. In the next stage, the central nervous spectrum of action of experimental K+ channel openers (PCO) was considered. As far as they have been studied, experimental K+ channel openers display a spectrum of action comparable to that of flupirtine. In the final stage, a global model was developed in which flupirtine stabilizes the resting membrane potential by activating inwardly rectifying K+ channels, thus indirectly inhibiting the activation of NMDA receptors. The model presented here reconciles the known functional NMDA receptor antagonism of flupirtine with the activation of K+ channels that occurs at therapeutic concentrations, thus providing an understanding of flupirtine's spectrum of action. This makes flupirtine the prototype of a clinically applicable substance group with analgesic, muscle-relaxant and neuroprotective properties.