19 research outputs found
Positive and Negative Allosteric Modulators of N-Methyl- d -aspartate (NMDA) Receptors:Structure-Activity Relationships and Mechanisms of Action
Synthesis of a series of novel 3,9-disubstituted phenanthrenes as analogues of known <i>N</i>-methyl-D-aspartate receptor allosteric modulators
9-Substituted phenanthrene-3-carboxylic acids have been reported to have allosteric modulatory activity at the NMDA receptor. This receptor is activated by the excitatory neurotransmitter L-glutamate and has been implicated in a range of neurological disorders such as schizophrenia, epilepsy and chronic pain and neurodegenerative disorders such as Alzheimer’s disease. Herein, the convenient synthesis of a wide range of novel 3,9-disubstituted phenanthrene derivatives starting from a few common intermediates is described. These new phenanthrene derivatives will help to clarify the structural requirements for allosteric modulation of the NMDA receptor
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The NMDA receptor intracellular C-terminal domains reciprocally interact with allosteric modulators
N-methyl-d-aspartate receptors (NMDARs) have multiple prominent roles in CNS function but their excessive or insufficient activity contributes to neuropathological/psychiatric disorders. Consequently, a variety of positive and negative allosteric modulators (PAMs and NAMs, respectively) have recently been developed. Although these modulators bind to extracellular domains, in the present report we find that the NMDAR's intracellular C-terminal domains (CTDs) significantly influence PAM/NAM activity. GluN2 CTD deletion robustly affected NAM and PAM activity with both enhancing and inhibiting effects that were compound-specific and NMDAR subunit-specific. In three cases, individual PAMs became NAMs at specific GluN2-truncated receptors. In contrast to GluN2, GluN1 CTD removal only reduced PAM activity of UBP684 and CIQ, and did not affect NAM activity. Consistent with these findings, agents altering phosphorylation state or intracellular calcium levels displayed receptor-specific and compound-specific effects on PAM activity. It is possible that the GluN2's M4 domain transmits intracellular modulatory signals from the CTD to the M1/M4 channel gating machinery and that this site is a point of convergence in the direct or indirect actions of several PAMs/NAMs thus rendering them sensitive to CTD status. Thus, allosteric modulators are likely to have a marked and varied sensitivity to post-translational modifications, protein-protein associations, and intracellular ions. The interaction between PAM activity and NMDAR CTDs appears reciprocal. GluN1 CTD-deletion eliminated UBP684, but not pregnenolone sulfate (PS), PAM activity. And, in the absence of agonists, UBP684, but not PS, was able to promote movement of fluorescently-tagged GluN1-CTDs. Thus, it may be possible to pharmacologically target NMDAR metabotropic activity in the absence of channel activation
Mechanism and properties of positive allosteric modulation of N-methyl-d-aspartate receptors by 6-alkyl 2-naphthoic acid derivatives
Multiple roles of GluN2B-containing NMDA receptors in synaptic plasticity in juvenile hippocampus
AbstractIn the CA1 area of the hippocampus N-methyl-d-aspartate receptors (NMDARs) mediate the induction of long-term depression (LTD), short-term potentiation (STP) and long-term potentiation (LTP). All of these forms of synaptic plasticity can be readily studied in juvenile hippocampal slices but the involvement of particular NMDAR subunits in the induction of these different forms of synaptic plasticity is currently unclear. Here, using NVP-AAM077, Ro 25-6981 and UBP145 to target GluN2A-, 2B- and 2D-containing NMDARs respectively, we show that GluN2B-containing NMDARs (GluN2B) are involved in the induction of LTD, STP and LTP in slices prepared from P14 rat hippocampus. A concentration of Ro (1 μM) that selectively blocks GluN2B-containing diheteromers is able to block LTD. It also inhibits a component of STP without affecting LTP. A higher concentration of Ro (10 μM), that also inhibits GluN2A/B triheteromers, blocks LTP. UBP145 selectively inhibits the Ro-sensitive component of STP whereas NVP inhibits LTP. These data are consistent with a role of GluN2B diheretomers in LTD, a role of both GluN2B- and GluN2D- containing NMDARs in STP and a role of GluN2A/B triheteromers in LTP.This article is part of the Special Issue entitled ‘Ionotropic glutamate receptors’
Effect of DNDS, picrotoxin and CsF-DIDS on evoked IPSCs.
<p>Upper panels of A-E: Example traces during the diffusion of K-Gluconate (A), K-Gluconate +DNDS (B), K-Gluconate +DNDS & CaCl<sub>2</sub> (C), K-Gluconate + picrotoxin (D) and Cs-Fluoride +DIDS (E) intracellular pipette solutions. Each trace shows the IPSC at the start of recording (black, time point i in middle panels), in the last minute before bath application of picrotoxin (magenta, time point ii in middle panels) and at the end of the bath application of picrotoxin (blue, time point iii in middle panels). Middle panels of A-E: Normalised IPSC amplitudes. Blue bar indicates the presence of bath picrotoxin (PTX). Lower panels of A-D: Corresponding series resistance during experiments. NBQX and AP5 were present throughout the experiments. E) Group data of the normalised evoked IPSC amplitudes for the four intracellular pipette solutions, taken at time point ii, individual data points marked as magenta dots. Summary statistics represent tests comparing the normalised evoked IPSC amplitudes at time point ii with the normalised baseline amplitude for each data set. Data are plotted as mean ± SEM.</p
Effect of Fluoride on spontaneous and evoked EPSCs.
<p>A-B) Example traces (upper panel) of sharp waves (black) and corresponding spontaneous EPSCs from the 1<sup>st</sup> (left, grey) and last (right, magenta) 5 minutes of recording in K-Gluconate (A) and K-Fluoride (B) intracellular pipette solutions. Lower panel: Group normalised EPSC amplitude time course, during wash-in. Grey bar (time point i) and magenta bar (time point ii) indicate the times during which the example traces in the upper panels are taken from. Upper panels of D-E): Example traces of pharmacologically isolated, evoked EPSCs during the wash-in of K-Gluconate (D) and K-Fluroride (E). Each trace shows the EPSC at the start of wash-in (black, time point i in middle panels) and at the end of the wash-in period (magenta, time point ii in middle panels). Middle panels of D-E: Normalised EPSC amplitudes during wash-in. Lower panels of D-E: Corresponding series resistance during wash-in. Picrotoxin was present in the bath throughout the experiments. C&F) Average group data of the normalised EPSC amplitudes, taken in the last 5 minutes of recording for the spontaneous (C) and evoked (F) EPSCs, individual data points marked by magenta dots. Summary statistics represent tests comparing the normalised EPSC amplitudes in the last 5 minutes of recording with the normalised baseline amplitude for each data set. Data are plotted as mean ± SEM.</p