title: Concomitant manipulation of murine NMDA- and AMPA-receptors to produce pro-cognitive drug effects in mice.
abstract: Bifunctional drug therapy targeting distinct receptor signalling systems can generate increased efficacy at lower concentrations compared to monofunctional therapy. Non-competitive blockade of the NMDA receptors or the potentiation of AMPA receptors is well documented to result in memory enhancement. Here, we compared the efficacy of the low-affinity NMDA receptor blocker memantine or the positive modulator of AMPA receptor QXX (in C57BL/6J at 1 or 5mg/kg, ip) with new derivatives of isothiourea (0.5-1 mg/kg, ip) that have bifunctional efficacy. Low-affinity NMDA blockade by these derivatives was achieved by introducing greater flexibility into the molecule, and AMPA receptor stimulation was produced by a sulfamide-containing derivative of isothiourea. Contextual learning was examined in a step-down avoidance task and extinction of contextual memory was studied in a fear-conditioning paradigm. Memantine enhanced contextual learning while QXX facilitated memory extinction; both drugs were effective at 5 mg/kg. The new derivative IPAC-5 elevated memory scores in both tasks at the dose 0.5 mg/kg and exhibited the lowest IC₅₀ values of NMDA receptor blockade and highest potency of AMPA receptor stimulation. Thus, among the new drugs tested, IPAC-5 replicated the properties of memantine and QXX in one administration with increased potency. Our data suggest that a concomitant manipulation of NMDA- and AMPA-receptors results in pro-cognitive effects and supports the concept bifunctional drug therapy as a promising strategy to replace monofunctional therapies with greater efficacy and improved compliance.
authors.affiliation: School for Mental Health and Neuroscience, Department of Neuroscience, Maastricht University, Universiteitssingel 40, NL 6229ER Maastricht, Netherlands; GIGA Neuroscience, University of Liege, Avenu de l'Hopital 1, B36 4000 Liege, Belgium.
authors.forename: Julie
authors.initials: J
authors.lastname: Vignisse
authors.affiliation: School for Mental Health and Neuroscience, Department of Neuroscience, Maastricht University, Universiteitssingel 40, NL 6229ER Maastricht, Netherlands.
authors.forename: Harry W M
authors.initials: HW
authors.lastname: Steinbusch
authors.affiliation: Institute of Physiologically Active Compounds, Laboratory of Neurochemistry, Russian Academy of Sciences, Chernogolovka, Severnii proesd 1, 142432 Moscow Region, Russia.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Grigoriev
authors.affiliation: Institute of Physiologically Active Compounds, Laboratory of Neurochemistry, Russian Academy of Sciences, Chernogolovka, Severnii proesd 1, 142432 Moscow Region, Russia.
authors.forename: Alexei
authors.initials: A
authors.lastname: Bolkunov
authors.affiliation: Institute of Physiologically Active Compounds, Laboratory of Neurochemistry, Russian Academy of Sciences, Chernogolovka, Severnii proesd 1, 142432 Moscow Region, Russia.
authors.forename: Alexey
authors.initials: A
authors.lastname: Proshin
authors.affiliation: GIGA Neuroscience, University of Liege, Avenu de l'Hopital 1, B36 4000 Liege, Belgium.
authors.forename: Lucien
authors.initials: L
authors.lastname: Bettendorff
authors.affiliation: Institute of Physiologically Active Compounds, Laboratory of Neurochemistry, Russian Academy of Sciences, Chernogolovka, Severnii proesd 1, 142432 Moscow Region, Russia. Electronic address: sergeybachurin@yahoo.com.
authors.forename: Sergey
authors.initials: S
authors.lastname: Bachurin
authors.affiliation: School for Mental Health and Neuroscience, Department of Neuroscience, Maastricht University, Universiteitssingel 40, NL 6229ER Maastricht, Netherlands.
authors.forename: Tatyana
authors.initials: T
authors.lastname: Strekalova
mesh_terms: D000498:Allyl Compounds / Q000494:pharmacology*; D000818:Animals; D001007:Anxiety / Q000188:drug therapy; D001362:Avoidance Learning / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000502:physiology; D003213:Conditioning, Psychological / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D005108:Extinction, Psychological / Q000187:drug effects; D005239:Fear / Q000187:drug effects; D066298:In Vitro Techniques; D007858:Learning / Q000187:drug effects*; D008297:Male; D008559:Memantine / Q000008:administration & dosage / Q000494:pharmacology; D008568:Memory / Q000187:drug effects*; D011939:Mental Recall / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D051381:Rats; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013890:Thiourea / Q000031:analogs & derivatives* / Q000494:pharmacology
chemical_list: C540177:3-allyl-1,1-dibenzyl-2-ethylisothiourea; D000498:Allyl Compounds; D018691:Excitatory Amino Acid Antagonists; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D013890:Thiourea; D008559:Memantine
keywords: Low-affinity NMDA receptor blockade; Mouse; Multi-target mechanism; Positive modulation of AMPA receptor