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Concomitant manipulation of murine NMDA- and AMPA-receptors to produce pro-cognitive drug effects in mice.
Eur Neuropsychopharmacol. 2014 Feb; 24(2):309-20.EN

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+Show Affiliations

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.School for Mental Health and Neuroscience, Department of Neuroscience, Maastricht University, Universiteitssingel 40, NL 6229ER Maastricht, Netherlands.Institute of Physiologically Active Compounds, Laboratory of Neurochemistry, Russian Academy of Sciences, Chernogolovka, Severnii proesd 1, 142432 Moscow Region, Russia.Institute of Physiologically Active Compounds, Laboratory of Neurochemistry, Russian Academy of Sciences, Chernogolovka, Severnii proesd 1, 142432 Moscow Region, Russia.Institute of Physiologically Active Compounds, Laboratory of Neurochemistry, Russian Academy of Sciences, Chernogolovka, Severnii proesd 1, 142432 Moscow Region, Russia.GIGA Neuroscience, University of Liege, Avenu de l'Hopital 1, B36 4000 Liege, Belgium.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.School for Mental Health and Neuroscience, Department of Neuroscience, Maastricht University, Universiteitssingel 40, NL 6229ER Maastricht, Netherlands.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

23993168

Citation

Vignisse, Julie, et al. "Concomitant Manipulation of Murine NMDA- and AMPA-receptors to Produce Pro-cognitive Drug Effects in Mice." European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology, vol. 24, no. 2, 2014, pp. 309-20.
Vignisse J, Steinbusch HW, Grigoriev V, et al. Concomitant manipulation of murine NMDA- and AMPA-receptors to produce pro-cognitive drug effects in mice. Eur Neuropsychopharmacol. 2014;24(2):309-20.
Vignisse, J., Steinbusch, H. W., Grigoriev, V., Bolkunov, A., Proshin, A., Bettendorff, L., Bachurin, S., & Strekalova, T. (2014). Concomitant manipulation of murine NMDA- and AMPA-receptors to produce pro-cognitive drug effects in mice. European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology, 24(2), 309-20. https://doi.org/10.1016/j.euroneuro.2013.06.010
Vignisse J, et al. Concomitant Manipulation of Murine NMDA- and AMPA-receptors to Produce Pro-cognitive Drug Effects in Mice. Eur Neuropsychopharmacol. 2014;24(2):309-20. PubMed PMID: 23993168.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Concomitant manipulation of murine NMDA- and AMPA-receptors to produce pro-cognitive drug effects in mice. AU - Vignisse,Julie, AU - Steinbusch,Harry W M, AU - Grigoriev,Vladimir, AU - Bolkunov,Alexei, AU - Proshin,Alexey, AU - Bettendorff,Lucien, AU - Bachurin,Sergey, AU - Strekalova,Tatyana, Y1 - 2013/08/07/ PY - 2012/12/24/received PY - 2013/06/18/revised PY - 2013/06/23/accepted PY - 2013/9/3/entrez PY - 2013/9/3/pubmed PY - 2014/10/22/medline KW - Low-affinity NMDA receptor blockade KW - Mouse KW - Multi-target mechanism KW - Positive modulation of AMPA receptor SP - 309 EP - 20 JF - European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology JO - Eur Neuropsychopharmacol VL - 24 IS - 2 N2 - 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. SN - 1873-7862 UR - https://www.unboundmedicine.com/medline/citation/23993168/Concomitant_manipulation_of_murine_NMDA__and_AMPA_receptors_to_produce_pro_cognitive_drug_effects_in_mice_ DB - PRIME DP - Unbound Medicine ER -