Kaniakova M(1), Korabecny J(2), Holubova K(3), Kleteckova L(3), Chvojkova M(3), Hakenova K(4), Prchal L(5), Novak M(6), Dolezal R(5), Hepnarova V(7), Svobodova B(2), Kucera T(7), Lichnerova K(1), Krausova B(8), Horak M(9), Vales K(10), Soukup O(11).

Affiliation

Kaniakova M(1), Korabecny J(2), Holubova K(3), Kleteckova L(3), Chvojkova M(3), Hakenova K(4), Prchal L(5), Novak M(6), Dolezal R(5), Hepnarova V(7), Svobodova B(2), Kucera T(7), Lichnerova K(1), Krausova B(8), Horak M(9), Vales K(10), Soukup O(11).
Author information:
(1)Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 14220 Prague 4, Czech Republic; Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 14220 Prague 4, Czech Republic.
(2)Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
(3)Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 14220 Prague 4, Czech Republic; National Institute of Mental Health, Topolová 748, 250 67 Klecany, Czech Republic.
(4)National Institute of Mental Health, Topolová 748, 250 67 Klecany, Czech Republic.
(5)Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic.
(6)Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic; Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Faculty of Pharmacy, Charles University, Akademika Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic.
(7)Department of Toxicology and Military Pharmacy, Faculty of Military Health Sciences, University of Defence, Trebesska 1575, 500 01 Hradec Kralove, Czech Republic.
(8)Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 14220 Prague 4, Czech Republic.
(9)Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 14220 Prague 4, Czech Republic; Institute of Experimental Medicine of the Czech Academy of Sciences, Videnska 1083, 14220 Prague 4, Czech Republic. Electronic address: [Email]
(10)Institute of Physiology of the Czech Academy of Sciences, Videnska 1083, 14220 Prague 4, Czech Republic; National Institute of Mental Health, Topolová 748, 250 67 Klecany, Czech Republic. Electronic address: [Email]
(11)Biomedical Research Center, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove, Czech Republic. Electronic address: [Email]

Abstract

N-methyl-D-aspartaterecepro receptor (NMDARs) are a subclass of glutamate receptors, which play an essential role in excitatory neurotransmission, but their excessive overactivation by glutamate leads to excitotoxicity. NMDARs are hence a valid pharmacological target for the treatment of neurodegenerative disorders; however, novel drugs targeting NMDARs are often associated with specific psychotic side effects and abuse potential. Motivated by currently available treatment against neurodegenerative diseases involving the inhibitors of acetylcholinesterase (AChE) and NMDARs, administered also in combination, we developed a dually-acting compound 7-phenoxytacrine (7-PhO-THA) and evaluated its neuropsychopharmacological and drug-like properties for potential therapeutic use. Indeed, we have confirmed the dual potency of 7-PhO-THA, i.e. potent and balanced inhibition of both AChE and NMDARs. We discovered that it selectively inhibits the GluN1/GluN2B subtype of NMDARs via an ifenprodil-binding site, in addition to its voltage-dependent inhibitory effect at both GluN1/GluN2A and GluN1/GluN2B subtypes of NMDARs. Furthermore, whereas NMDA-induced lesion of the dorsal hippocampus confirmed potent anti-excitotoxic and neuroprotective efficacy, behavioral observations showed also a cholinergic component manifesting mainly in decreased hyperlocomotion. From the point of view of behavioral side effects, 7-PhO-THA managed to avoid these, notably those analogous to symptoms of schizophrenia. Thus, CNS availability and the overall behavioral profile are promising for subsequent investigation of therapeutic use.