Preferential Inhibition of Tonically over Phasically Activated NMDA Receptors by Pregnane Derivatives

Abstract

Postsynaptic N-methyl-D-aspartate receptors (NMDARs) phasically activated by presynaptically released glutamate are critical for synaptic transmission and plasticity. However, under pathological conditions, excessive activation of NMDARs by tonically increased ambient glutamate contributes to excitotoxicity associated with various acute and chronic neurological disorders. Here, using heterologously expressed GluN1/GluN2A and GluN1/GluN2B receptors and rat autaptic hippocampal microisland cultures, we show that pregnanolone sulfate inhibits NMDAR currents induced by a prolonged glutamate application with a higher potency than the NMDAR component of EPSCs. For synthetic pregnanolone derivatives substituted with a carboxylic acid moiety at the end of an aliphatic chain of varying length and attached to the steroid skeleton at C3, the difference in potency between tonic and phasic inhibition increased with the length of the residue. The steroid with the longest substituent, pregnanolone hemipimelate, had no effect on phasically activated receptors while inhibiting tonically activated receptors. In behavioral tests, pregnanolone hemipimelate showed neuroprotective activity without psychomimetic symptoms. These results provide insight into the influence of steroids on neuronal function and stress their potential use in the development of novel therapeutics with neuroprotective action.

Neurosteroids as Selective Inhibitors of Glycine Receptor Activity: Structure-Activity Relationship Study on Endogenous Androstanes and Androstenes

“…In our opinion, the acceleration of the I Gly decay can be explained by the slow block of the open channel or/and the acceleration of the desensitization gate (Gielen et al, 2015). Other authors (Borovska et al, 2012;Vyklicky et al, 2016) described the acceleration of the decay of NMDA current under the influence of NS and explain this effect by slow NS diffusion to the site of action at the extracellular vestibule of the NMDAR. At present, we cannot give preference to any of these assumptions regarding the mechanisms for accelerating the desensitization of I Gly under the influence of NS.…”

Neurosteroid biosynthesis down‐regulation and changes in GABAA receptor subunit composition: a biomarker axis in stress‐induced cognitive and emotional impairment

“…Synaptic activation of NMDA receptors is important for synaptic plasticity, learning and memory, and synaptogenesis, whereas tonic NMDA receptor activation is generally associated with excitotoxicity. Consistently, PAS's negative regulation of tonic NMDA neurotransmission has recently been reported to provide neuroprotection in vivo in a manner that is devoid of unwanted psychotomimetic effects (Vyklicky et al, ). This feature is highly relevant for developing a novel class of steroid‐based NMDA‐inhibitor therapeutics, which lack the side effects that plague the use of classical NMDA receptor inhibitors, including ketamine and congeners.…”

“…This feature is highly relevant for developing a novel class of steroid‐based NMDA‐inhibitor therapeutics, which lack the side effects that plague the use of classical NMDA receptor inhibitors, including ketamine and congeners. Based on this mechanism of action, a number of PAS analogues have been recently synthesized, including the amide‐based analogues (Adla et al, ) and pregnanolone hemipimelate that has no action at phasic and synaptic NMDA receptors but shows a strong selectivity (several folds higher than PAS) in inhibiting tonic‐activated receptors (Vyklicky et al, ).…”

Memantine Derivatives as Multitarget Agents in Alzheimer’s Disease

“…Furthermore, the urea derivative 2 showed the highest inhibition of Aβ 1-40 aggregation, while the thiourea 1 inhibits NMDAR with a similar IC 50 value as memantine (1.80 μM vs. 1 μM) and the same efficacy as open channel blocker, but with slower kinetics, which may suggest why it preferentially binds to eNMDAR [ 31 ]. In fact, selectivity for eNMDARs is highly desirable due to their involvement in glutamate-mediated excitotoxicity and it is achieved through use-dependent inhibitors with a slow onset of action [ 32 ]. In addition to these activities, most of the compounds tested displayed weak-to-moderate activity towards BACE-1 enzyme, which, alongside inhibitory activity on Aβ 1-40 aggregation previously showed, proves their potential antiamyloid properties.…”