A common mechanism allows selective targeting of GluN2B subunit-containing N-methyl-D-aspartate receptors

Abstract

N-methyl-D-aspartate receptors (NMDARs), especially GluN2B-containing NMDARs, are associated with neurodegenerative diseases like Parkinson, Alzheimer and Huntington based on their high Ca2+ conductivity. Overactivation leads to high intracellular Ca2+ concentrations and cell death rendering GluN2B-selective inhibitors as promising drug candidates. Ifenprodil represents the first highly potent prototypical, subtype-selective inhibitor of GluN2B-containing NMDARs. However, activity of ifenprodil on serotonergic, adrenergic and sigma receptors limits its therapeutic use. Structural reorganization of the ifenprodil scaffold to obtain 3-benzazepines retained inhibitory GluN2B activity but decreased the affinity at the mentioned non-NMDARs. While scaffold optimization improves the selectivity, the molecular inhibitory mechanism of these compounds is still not known. Here, we show a common inhibitory mechanism of ifenprodil and the related 3-benzazepines by mutational modifications of the receptor binding site, chemical modifications of the 3-benzazepine scaffold and subsequent in silico simulation of the inhibitory mechanism.

Conjugation of Aminoadamantane and γ-Carboline Pharmacophores Gives Rise to Unexpected Properties of Multifunctional Ligands

“…The NR2B subunit is involved in neurodegenerative processes in patients with Parkinson’s and Huntington’s diseases as well as AD [ 33 ]. Therefore, efficient modulators of GluN2B-containing NMDARs are a promising tool for further investigation and potential treatment of these diseases [ 34 , 35 , 36 ].…”

Lack of Glutamate Receptor Subunit Expression Changes in Hippocampal Dentate Gyrus after Experimental Traumatic Brain Injury in a Rodent Model of Depression

“…When upregulated, GluN2B can hinder the neuronal network remodeling response to plasticity [ 66 ]. Increases in GluN2B have also been shown to be related to neurodegenerative pathways in diseases such as Parkinson’s, Alzheimer’s, and Huntington’s disease [ 67 ]. Whether the increase in GluN2B after experimental TBI is related to the later development of post-TBI neurodegeneration is unknown.…”

Role of NR2B/ERK signaling in the neuroprotective effect of dexmedetomidine against sevoflurane induced neurological dysfunction in the developing rat brain

“…It is observed that continued NMDAR activation can lead to neuronal injury [20]. Unbalance of NMDARs is widely suggested to be associated with the occurrence and development of various central nervous system diseases, such as ischemic stroke, Alzheimer disease, Parkinson disease and so on [19,21]. NR2B is a subtype of NMDAR, which is associated with the over activation of NMDAR, followed by the neuronal damage [22].…”