Molecular and Cellular Pharmacology The inhibitory potency of local anesthetics on NMDA receptor signalling depends on their structural features Carsten Gronwald a, 1 , Vladimir Vegh a, b, 1, 2 , Markus W. Hollmann c , Anke Hahnenkamp a , Vladimir Garaj b , Klaus Hahnenkamp a, ⁎ a Dept. of Anesthesiology and Intensive Care, Albert-Schweitzer-Campus 1, Building A1, University Hospital, 48149 Muenster, Germany b Department of Pharmaceutical Chemistry, Comenius University, Kalinciakova 8 3rd floor, 83232 Bratislava, Slovakia c Department of Anesthesiology, University of Amsterdam, Meibergdreef 9, Postbus 22660 H1Z-112, 1100 DD Amsterdam, The Netherlands abstract article info Article history: Received 15 July 2011 Received in revised form 13 October 2011 Accepted 27 October 2011 Available online 4 November 2011 Keywords: Anesthetics local Pain Neuropathic Potency Analgesic Theories Ion Ion channel Pharmacology NMDA receptor signaling 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 10 min incubation with in total 13 experimental derivates of local anesthetics (10 -3 M–10 -7 M) were measured to obtain the IC 50 . Fur- thermore 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 in- hibition 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. © 2011 Elsevier B.V. All rights reserved. 1. Introduction The treatment of hyperalgesic pain states due to tissue or nerve injury after surgery remains a clinical challenge. The mechanisms of the devel- opment of hyperalgesic pain states are not completely understood, but the involvement of N-methyl-D-aspartate (NMDA) receptor signaling in the brain and the spinal cord leading to central changes in synaptic excit- ability is strongly suggested (Kaneko et al., 2011; Sandkuhler et al., 2000; Sang, 2000). NMDA receptors are widely distributed in the central ner- vous system and are protein complexes composed of two classes of sub- units, the essential subunit GluN1 and the modulating GluN2 subunit (of which four different types exist: A–D). The GluN2 subunits alone cannot form functional channels, but they amplify GluN1 activity and induce functional variability in NMDA receptor signaling. These subunits co- assemble in various combinations to form functionally distinct NMDA re- ceptors (Cull-Candy and Leszkiewicz, 2004). In the present study, the GluN1 subunit was co-expressed with the GluN2A subunit. This combi- nation is widely distributed in the brain and the dorsal horn of the spinal cord and is believed to play a relevant physiological role in the develop- ment of hyperalgesia and acute opioid tolerance (Kaneko et al., 2011; Sandkuhler et al., 2000). Inhibition of NMDA receptors may minimize the development of these neuropathic pain states and therefore is a potential therapeutical target. Currently, most agents initiate several side effects like memory impairment and ataxia (Parsons, 2001). Studies in volunteers provide evidence that local anesthetics mini- mize hyperalgesia by a central mode of action which makes an interac- tion between local anesthetics and NMDA receptors likely (Koppert et al., 2000). In addition inhibition of NMDA receptor function by local an- esthetics was demonstrated repeatedly in several in-vitro models European Journal of Pharmacology 674 (2012) 13–19 ⁎ Corresponding author. Tel.: + 49 251 83 47255; fax: + 49 251 83 48667. E-mail addresses: gronwac@uni-muenster.de (C. Gronwald), vegh@zoznam.sk (V. Vegh), m.w.hollmann@amc.nl (M.W. Hollmann), anke.hahnenkamp@uni-muenster.de (A. Hahnenkamp), garajv@fpharm.uniba.sk (V. Garaj), klaus.hahnenkamp@ukmuenster.de (K. Hahnenkamp). 1 Those authors contributed equally. 2 Present address. 0014-2999/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.ejphar.2011.10.035 Contents lists available at SciVerse ScienceDirect European Journal of Pharmacology journal homepage: www.elsevier.com/locate/ejphar