High throughput screen to identify small molecule analgesics targeting nNOS-NOS1AP protein-protein interactions

Abstract This application High throughput screen to identify small molecule analgesics targeting nNOS NOS AP protein protein interactions addresses the critical need for more effective medications to treat pain and in particular chronic and neuropathic pain Pain is the single most common reason Americans access the health care system Chronic pain affects million people in the USA Current pain medications such as NSAIDS steroids opiates and gabapentin analogues have documented side effects are ineffective in neuropathic pain or work only in subsets of patients Chronic pain results in socioeconomic costs estimated at $ billion annually Activation of NMDA receptors NMDAR induces neuronal cell death and mediates central nervous system sensitization which is implicated in the development and maintenance of pathological pain NMDA induced excitotoxicity depends on formation of a multi protein cascade complex at the receptor Activation of the NMDAR leads to the recruitment of neuronal nitric oxide synthase nNOS by the post synaptic density protein PSD to the signaling pathways which ultimately leads to neuronal cell death Peptide disruptors of the NMDAR tripartite complex have been shown to be efficacious in stroke models and may also have fewer side effects than broad NMDAR antagonists Small molecule inhibitors targeting the complex have potential as effective analgesics without the side effects associated with broad inhibition of NMDAR A direct downstream effector of the NMDAR complex is nNOS NOS AP A compound inhibiting this complex will likely be efficacious against stroke neuropathic pain and other chronic neurological diseases precipitated by excitotoxicity Anagin and its research partners at Indiana University have established a robust high quality high throughput assay to identify small molecule disruptors of nNOS NOS AP interaction validated the assay and our approach in a pilot compound small molecule library screen In addition Anagin has secondary in vitro selectivity and cell based efficacy assays to perform hit to lead compound characterization as well as established collaborations to perform preclinical validation In this Phase I SBIR program the team will run an extensive small molecule screen to identify new druggable inhibitors with novel scaffolds that target nNOS NOS AP Anagin will complete a small chemistry effort and initial administration distribution metabolism excretion toxicity studies to determine which compound series to advance as a lead molecule in a Phase II SBIR program for the treatment of chronic and neuropathic pain Project Narrative Pain is the single most common reason Americans access the health care system and affects million people in the U S A Current pain medications such as NSAIDS steroids opiates and gabapentin have side effects are ineffective in neuropathic pain or only work in some of the patients that need pain control In this SBIR Anagin will screen a small molecule library and identify new lead compounds that will be effective again pain especially neuropathic pain with fewer side effects than current treatments