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National Repository of Grey Literature

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The study of functional and molecular properties of NMDA receptors Vyklický, Vojtěch ; Vyklický, Ladislav (advisor) ; Chvátal, Alexandr (referee) ; Tureček, Rostislav (referee) N-methyl-D-aspartate (NMDA) receptors are a subtype of ionotropic glutamate receptors, which mediate fast synaptic transmission in the vertebrate central nervous system and play a key role in synaptic plasticity. NMDA receptor overexcitation leads to cell death that underlies many serious neurological and psychiatric disorders. The aim of our research was to characterize novel drugs that modulate NMDAR activity. We have tested a series of newly synthesized steroidal compounds for their activity on recombinant receptors. We have demonstrated a relationship between the structure of the analogues of a naturally occurring neurosteroid pregnanolone sulfate and their ability to modulate NMDA receptors. The results of our experiments characterize the role of substituents at the steroid A and D ring. We have found specific substituents on carbons C3 and C17 of the steroidal skeleton that lead to a substantial increase of steroid efficacy and the ability to positively affect the ratio between the inhibition of stationary and non-stationary receptor activation. These two states represent receptors long-term activated (tonically) and synaptically activated (phasically), respectively. Using electrophysiological and optical methods in combination with mathematical modeling we have shown that the plasma membrane plays an... Detailed record

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