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
PY - 2014/2
Y1 - 2014/2
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 blacker memantine or the positive modulator of AMPA receptor QXX (in C57BL/6 J at 1 or 5 mg/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.
AB - 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 blacker memantine or the positive modulator of AMPA receptor QXX (in C57BL/6 J at 1 or 5 mg/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.
KW - Low-affinity NMDA receptor blockade
KW - Positive modulation of AMPA receptor
KW - Multi-target mechanism
KW - Mouse
U2 - 10.1016/j.euroneuro.2013.06.010
DO - 10.1016/j.euroneuro.2013.06.010
M3 - Article
C2 - 23993168
SN - 0924-977X
VL - 24
SP - 309
EP - 320
JO - European Neuropsychopharmacology
JF - European Neuropsychopharmacology
IS - 2
ER -