Small molecule inhibitors of PSD95-nNOS protein-protein interactions as novel analgesics.

摘要: Aberrant increases in NMDA receptor (NMDAR) signaling contributes to central nervous system sensitization and chronic pain by activating neuronal nitric oxide synthase (nNOS) generating (NO). Because the scaffolding protein postsynaptic density 95kDA (PSD95) tethers nNOS NMDARs, PSD95-nNOS complex represents a therapeutic target. Small molecule inhibitors IC87201 (EC5O: 23.94 μM) ZL006 (EC50: 12.88 directly inhibited binding of purified PSD95 proteins AlphaScreen without altering ErbB4. Both suppressed glutamate-induced cell death with efficacy comparable MK-801. preferentially phase 2A behavior formalin test allodynia induced intraplantar complete Freund's adjuvant administration. mechanical cold chemotherapeutic agent paclitaxel (ED50s: 2.47 0.93 mg/kg i.p. for ZL006, respectively). Efficacy disruptors was similar Motor ataxic effects were MK-801 but not or IC87201. Finally, produced hyperalgesia tail-flick whereas did alter basal nociceptive thresholds. Our studies establish utility using pairs quantify disruption protein-protein interactions. results demonstrate previously unrecognized antinociceptive establish, two small molecules, broad application treating neuropathic inflammatory pain. Collectively, our that disrupting interactions is effective attenuating pathological producing unwanted side (i.e. motor ataxia) associated NMDAR antagonists.