A novel NMDA receptor test model based on hiPSC-derived neural cells

Abstract

N-Methyl-D-aspartate receptors (NMDARs) are central for learning and information processing in the brain. Dysfunction of NMDARs can play a key role in the pathogenesis of neurodegeneration and drug addiction. The development of selective NMDAR modulators represents a promising strategy to target these diseases. Among such modulating compounds are ifenprodil and its 3-benzazepine derivatives. Classically, the effects of these NMDAR modulators have been tested by techniques like two-electrode voltage clamp (TEVC), patch clamp, or fluorescence-based assays. However, testing their functional effects in complex human systems requires more advanced approaches. Here, we established a human induced pluripotent stem cell-derived (hiPSC-derived) neural cell system and proved its eligibility as a test system for investigating NMDAR modulators and pharmaceutical effects on human neurons.

Pharmacological Potential of 3-Benzazepines in NMDAR-Linked Pathophysiological Processes

“…Modification in the tetramethylene spacer or its benzene ring and testing of these compounds revealed various potent NMDAR inhibitors, i.e., (R)-OF-NB1, (S)-OF-NB1, and PF-NB1. Furthermore, the inhibitory activity of these identified compounds was confirmed on human induced pluripotent stem cell (hiPSC) derived glutamatergic neurons as a physiological test system [59]. (R)-OF-NB1, a WMS-1410 derivative, was established as a selective NMDAR antagonist with significant NMDAR splice variant preference [68].…”

“…Ifenprodil (2-(4-benzylpiperidin-1-yl)-1-(4-hydroxyphenyl)-propan-1-ol), an active ingredient contained in vasodilator drugs (Cerocral, Dilvax, Vadilex), has been known since 1971 [57]. It was discovered that the alkyl spacer had a major impact on NMDAR inhibition, with IC 50 of 178.4 nM and binding affinities of 10 nM for GluN1-1a/GluN2B-containing receptors [58,59]. However, the benzylic OH − group was not required for the activity.…”

“…(R)-OF-NB1, a WMS-1410 derivative, was established as a selective NMDAR antagonist with significant NMDAR splice variant preference [68]. (R)-OF-NB1 and PF-NB1 were developed successfully as GluN2B-selective and powerful inhibitors (IC 50 for GluN1-1a/GluN2B of 97 nM and 60.9 nM [59,68]), and their application as positron emission tomography (PET) tracers was confirmed [69][70][71][72][73]. Because of its high blood-brain barrier permeability, 18 F-OF-NB1 builds up in areas of the brain where GluN2B is abundant.…”

The Potential of Human Induced Pluripotent Stem Cells (hiPSCs) for the Study of Channelopathies: Advances and Future Directions

“…For the differentiation of neuronal cell tissues, optimized protocols have been developed that allow stem cells to differentiate into specific neuronal cell types such as neurons, astrocytes, and oligodendrocytes. By combining specific growth factors and culture conditions, the desired electrophysiological properties can be studied [46][47][48].…”

“…By using stem cell-derived tissues, more comprehensive studies can be conducted on the effects of drugs on complex cell systems, leading to improved prediction of effects on the human body. This is particularly relevant for testing the efficacy and safety of potential therapeutic compounds in a disease-relevant context [48,55].…”