DEVELOPMENT OF A NOVEL OPEN-CHANNEL BLOCKER FOR GLUN1/GLUN2 NMDA RECEPTORS: MECHANISM AND PHARMACOLOGY

The N-methyl-D-aspartate receptor (NMDAR) is a subtype of glutamate receptor, mediating the primary excitatory neurotransmission in the human brain. It plays a crucial role in synaptic plasticity, a fundamental neural process believed to underlie learning and memory. Dysregulation of NMDAR function has been implicated in various psychiatric and neurological disorders.
Open-channel blockers of NMDARs have been explored as potential therapeutics for various neurological and neuropsychiatric disorders. In this study, we developed and electrophysiologically characterized a novel derivative of MK-801, designated K2060. Unlike MK-801, K2060 does not exhibit irreversible binding within the ion channel pore of GluN1/GluN2 NMDARs, while retaining strong inhibitory efficacy even in the presence of 1 mM Mg²⁺.
We showed that K2060 exhibits membrane-to-channel inhibition (MCI), which is another way in which open-channel blockers can enter NMDARs. It should be mentioned that the MCI mechanism of K2060 is distinct from that of memantine, in which it was first described.
We further evaluated the therapeutic potential of K2060 in a mouse model of tabun poisoning. When administered alongside standard antidotes (trimedoxime and atropine), K2060 significantly improved treatment outcomes, highlighting its promise as a complementary neuroprotective agent. Thus, K2060 showed promising results against severe organophosphate-induced seizures and could represent a new class of NMDAR inhibitors with unique inhibitory properties that could find application in other pathologies associated with the dysregulation of NMDARs.