CNS4 causes subtype ‐specific changes in agonist efficacy and reversal potential of permeant cations in NMDA receptors

Working hypothesis of CNS4 mechanism of action: Changes in glutamate concentration alter agonist binding domain (ABD) intersubunit interaction, that plays a crucial role in desensitization leading to channel constriction. CNS4 (blue) preferentially reverses the low glutamate (broken heart) induced changes in ABD conformation back to normal glutamate-like ABD conformation facilitating cation influx through the NMDA receptor channel. This will be experimentally evaluated in the future. AbstractThe NMDA subtype of glutamate receptor serves as an attractive drug target for the treatment of disorders evolving from hyper- or hypoglutamatergic conditions. Compounds that optimize the function of NMDA receptors are of great clinical significance. Here, we present the pharmacological characterization of a biased allosteric modulator, CNS4. Results indicate that CNS4 sensitizes ambient levels of agonists and reduces higher-concentration glycine& glutamate efficacy in 1/2AB receptors, but minimally alters these parameters in diheteromeric 1/2A or 1/2B receptors. Glycine efficacy is increased in both 1/2C and 1/2D, while glutamate efficacy is decreased in 1/2C and unaltered in 1/2D. CNS4 does not affect the activity of competitive antagonist binding at glycine (DCKA) and glutamate (DL-AP5) sites; however, it decreases memantine potency in 1/2A receptors but not in 1/2D receptors. Current –voltage (I-V) relationship studies indicate that CNS4 potentiates 1/2A inward currents, a phenomeno...
Source: Pharmacology Research and Perspectives - Category: Drugs & Pharmacology Authors: Tags: ORIGINAL ARTICLE Source Type: research