Pain is a serious, debilitating condition that is under treated because of the dose limiting side effects of currently used opiate therapeutics including respiratory depression, constipation, nausea, and physical dependence at therapeutic doses. Although arylacetamide K opioid agonists do not cause these side effects, they produce visual hallucinations and dysphoria. The endogenous agonist of the K opioid receptor, dynorphin A, and a stable peptide analog, E2078, produce analgesia in humans without causing dysphoria. The arylacetamides and dynorphins bind to different domains of the K receptor, which may result in the different in vivo pharmacological and clinically meaningful side effect profiles observed for these structurally diverse molecules. We propose to develop novel K receptor agonists that do not cause dysphoria by using differential binding to a chimeric receptor as a high-throughput screening tool. Compounds that bind to the K receptor in the same manner as dynorphin A and E2078 will then be tested in animals to determine whether they induce analgesia without causing the dysphoric side effects of previously developed arylacetamides that have been tested in man. Compounds that possess the desired pharmacological profile will be rapidly advanced into preclinical and clinical development. PROPOSED COMMERCIAL APPLICATION: Chronic pain.
