NMDAR-TRPM4 interaction interface inhibitor
NMDAR/TRPM4 interaction interface inhibitors, also known as ‘interface inhibitors’, are a class of neuroprotective small molecules discovered by Hilmar Bading and co-workers at Heidelberg University[1][2]. Their neuroprotective mode of action involves the disruption of a death signaling complex consisting of extrasynaptic NMDA receptors (NMDARs) and the transient receptor potential cation channel subfamily M member 4 (TRPM4). The NMDAR/TRPM4 complex is considered central to glutamate excitotoxicity, a neurodegenerative process shared by many neurological conditions including stroke, traumatic brain injury, Alzheimer’s disease, Amyotrophic Lateral Sclerosis (ALS), Huntington’s disease, and retinal degenerations[3][4]. The first interface inhibitors are compound 8/Brophenexin and compound 19/Aliudanexin (the suffix ‘-nexin’ indicates NMDA excitotoxicity inhibitor). They were identified in a computer-aided search for small molecules that, based on theoretical considerations, fit into the three-dimensional binding pocket formed by the portion of TRPM4, named TwinF, that forms the contact surface (‘interface’) with NMDARs in the NMDAR/TRPM4 complex formation. Compound 8/Brophenexin protects neurons from cell death in mouse models of stroke and retinal ganglion cell degeneration[1].
References
- ↑ 1.0 1.1 Yan, Jing; Bengtson, C. Peter; Buchthal, Bettina; Hagenston, Anna M.; Bading, Hilmar (9 October 2020). "Coupling of NMDA receptors and TRPM4 guides discovery of unconventional neuroprotectants". Science. 370 (6513): eaay3302. doi:10.1126/science.aay3302. ISSN 1095-9203. PMID 33033186 Check
|pmid=value (help). Unknown parameter|s2cid=ignored (help) - ↑ "New Class of Highly Effective Inhibitors Protects against Neurodegeneration – Heidelberg University". www.uni-heidelberg.de. Retrieved 2020-10-28.
- ↑ Bading, Hilmar (6 March 2017). "Therapeutic targeting of the pathological triad of extrasynaptic NMDA receptor signaling in neurodegenerations". The Journal of Experimental Medicine. 214 (3): 569–578. doi:10.1084/jem.20161673. ISSN 1540-9538. PMC 5339681. PMID 28209726.
- ↑ Parsons, Matthew P.; Raymond, Lynn A. (2014-04-16). "Extrasynaptic NMDA receptor involvement in central nervous system disorders". Neuron. 82 (2): 279–293. doi:10.1016/j.neuron.2014.03.030. ISSN 1097-4199. PMID 24742457. Unknown parameter
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