An Agonist Concentration Biased NMDA Receptor Modulator Produces Analgesic Activity in Experimental Animals

Abstract ID 87541 Poster Board 076 Pain is the most common reason for human adults to seek medical care. Pain restricts daily life activities, causes opioid addiction and depression, and affects quality of life. Imbalanced activity of NMDA glutamate receptor subtypes expressed in the excitatory and feedback inhibitory neurons leads to a hypoglutamatergic (low-glu) condition-mediated deactivation of the medial prefrontal cortex (mPFC). This low-glu condition is overcompensated by excessive glutamatergic activation and maladaptive plasticity, leading to hyperalgesia and allodynia. Therefore, treating low-glu mediated changes in neuronal circuit rearrangement by targeting specific NMDAR subtypes could be an ideal pain treatment strategy. GluN2A and GluN2D subtypes of NMDAR contribute to excitatory and feed-forward inhibitory neurotransmission, as they predominantly express on primary neurons and GABAergic interneurons in the mPFC, respectively. Therefore, prolonged pain sensation-mediated low-Glu condition could be corrected by concomitantly modulating GluN2A and GluN2D subunits in opposite directions. We have recently discovered a small molecule (CNS4) that modulates NMDAR subunits based on glutamate concentration. This compound preferentially potentiates neuroprotective GluN2A receptors by 22% and inhibits 35% of GluN2D when activated by 300μM glutamate. Conversely, CNS4 potentiates GluN2D currents by 8-fold when activated by 0.3μM glutamate. Similar glutamate dose-dependent activities of CNS4 on other GluN2 subtypes have recently been reported. Additionally, CNS4 increases the expression of GluN1 total protein in cultured rat brain cortical neurons by 1.4-fold. Furthermore, CNS42, a close congener of CNS4, increases the viability of primary cultured rat brain cortical (3.2x), striatal (2.7x), and cerebellar (1.5x) neurons. In a pharmacokinetic study, mice tolerated 100mg/kg IP administration of CNS4 that reached brain tissue within fifteen minutes. Remarkably, pharmacokinetics results indicate that more than 16% of CNS4 plasma concentration was detected in the brain tissue, with a Cmax of 3.3μg/ml. CNS4, a non-opioid compound, increased mice escape latency (paw-licking) in hotplate assay by 218% compared to saline control and 178% compared to positive control meloxicam. Currently, we are performing more medicinal chemistry and pharmacology studies to develop future analogs of CNS4 as clinically useful non-opioid analgesics.