7-Methoxyderivative of tacrine is a 'foot-in-the-door' open-channel blocker of GluN1/GluN2 and GluN1/GluN3 NMDA receptors with neuroprotective activity in vivo

0492869 - ÚEM 2019 RIV NL eng J - Článek v odborném periodiku
Kaniaková, Martina - Kletečková, L. - Lichnerová, Katarina - Holubová, K. - Skřenková, Kristýna - Kořínek, M. - Krůšek, J. - Smejkalová, T. - Korabecný, J. - Valeš, K. - Soukup, O. - Horák, Martin
7-Methoxyderivative of tacrine is a 'foot-in-the-door' open-channel blocker of GluN1/GluN2 and GluN1/GluN3 NMDA receptors with neuroprotective activity in vivo.
Neuropharmacology. Roč. 140, sep 15 (2018), s. 217-232. ISSN 0028-3908. E-ISSN 1873-7064
Institucionální podpora: RVO:68378041
Klíčová slova: behavioural experiment * electrophysiology * glutamate receptor * human pathogenic mutation * ion channel * pharmacology
Obor OECD: Neurosciences (including psychophysiology
Impakt faktor: 4.367, rok: 2018

N-methyl-D-aspartate receptors /NMDARs/ are ionotropic glutamate receptors that mediate excitatory neuro-transmission in the mammalian central nervous system /CNS/, and their dysregulation results in the aetiology of many CNS syndromes. Several NMDAR modulators have been used successfully in clinical trials /including memantine/ and NMDARs remain a promising pharmacological target for the treatment of CNS syndromes. 1,2,3,4-Tetrahydro-9-aminoacridine /tacrine, THA/ was the first approved drug for Alzheimers disease /AD/ treatment. 7-methoxyderivative of THA /7-MEOTA/ is less toxic and showed promising results in patients with tardive dyskinesia. We employed electrophysiological recordings in HEK293 cells and rat neurones to examine the mechanism of action of THA and 7-MEOTA at the NMDAR. We showed that both THA and 7-MEOTA are foot-in-the-door open-channel blockers of GluNl/GluN2 receptors and that 7-MEOTA is a more potent but slower blocker than THA. We found that the IC50 values for THA and 7-MEOTA exhibited the GluN1/GIuN2A < GluNl/G1uN2B < GluN1/GluN2C = GluN1/GluN2D relationship and that 7-MEOTA effectively inhibits human GluNl/GluN2A-M817V receptors that carry a pathogenic mutation. We also showed that 7-MEOTA is a foot-in-the-door open-channel blocker of GluNl/GluN3 receptors, although these receptors were not inhibited by memantine. In addition, the inhibitory potency of 7-MEOTA at synaptic and extrasynaptic hippocampal NMDAR5 was similar, and 7-MEOTA exhibited better neuroprotective activity when compared with THA and memantine in rats with NMDA-induced lesions of the hippocampus. Finally, intraperitoneal administration of 7-MEOTA attenuated MK-801-induced hyperlocomotion and pre-pulse inhibition deficit in rats. We conclude that 7-MEOTA may be considered for the treatment of diseases associated with the dysfunction of NMDARs.
Trvalý link: http://hdl.handle.net/11104/0294014