Eur J Pharmacol 2012 Jan 05;6741:13-9. doi: 10.1016/j.ejphar.2011.10.035.

The inhibitory potency of local anesthetics on NMDA receptor signalling depends on their structural features.

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Development of postoperative hyperalgesia depends on N-methyl-d-aspartate (NMDA) receptor activation. Local anesthetics protect against those hyperalgesic pain states and inhibit NMDA receptor activation. To outline what structural features of local anesthetics are responsible for NMDA receptor inhibition we evaluated a series of experimental lidocaine analogs (carbanilic derivates). Human GluN1/GluN2A NMDA receptors were expressed recombinantly in Xenopus laevis oocytes. Peak currents were measured by voltage clamp technique. Oocytes were stimulated with glutamate/glycine (EC(50)). The responses following a 10min incubation with in total 13 experimental derivates of local anesthetics (10(-3)M-10(-7)M) were measured to obtain the IC(50). Furthermore the Comprehensive Descriptors for Structural and Statistical Analysis CODESSA software was used to design a Quantitative Structure-Activity Relationship (QSAR)-model for all substances. The IC(50) values were in the range of 2.74×10(-5)M-2.26×10(-3)M, strongly affected by the position and the length of the aliphatic side chain in the aromatic part of the local anesthetic molecule. Substance with no substituent on the aromatic ring showed the highest inhibitory activity. The obtained QSAR model predicted that lidocaine derivatives with free positions 2 and 6 on the aromatic ring had a higher efficacy than clinically used local anesthetics for inhibition of NMDA receptor signaling. Structural changes of local anesthetic molecules can alter the potency to inhibit NMDA receptor signaling and are independent of the local anesthetic (sodium-channel blocking) potency. The development of novel drugs based on local anesthetic like structures may be a new approach for the protection or treatment of NMDA receptor mediated hyperalgesia and may be associated with a low side effect profile.

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