Buprenorphine analogs for the treatment of opioid abuse

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PROJECT SUMMARY The recent marked increase in misuse and abuse of opioids and the epidemic of opioid overdose mortality have greatly affected our society. Given that non-human primate models offer the most phylogenetically appropriate evaluation of opioid receptor functions and drug effects, the goal of this proposal is to establish a translational bridge for the functional profiles of buprenorphine analogs to ameliorate opioid-assoicated side effects in primates. Previous studies demonstrate that a buprenorphine analog BU08028 with mixed mu opioid peptide (MOP) and nociceptin/orphanin FQ peptide (NOP) partial agonist activities is a safe analgesic without abuse liablity. The proposal will further investigate the funcitional profiles of buprenorphine-inspired compounds, BU08028 and BU14003, in modulating three major aspects of opioid use disorder, i.e., abuse liability, relapse, and physical dependence. The proposal contains three aims: 1) To distinguish the functional profiles of buprenorphine-inspired compounds from opioids following acute and chronic administration. 2) To demonstrate the functional effectiveness of buprenorphine-inspired compounds to attenuate the abuse-related effects of opioids including oxycodone and heroin. 3) To demonstrate the functional effectiveness of buprenorphine-inspired compounds to alleviate the adverse effects from opioid dependence. These non- human primate behavioral assays have been designed specifically to reflect the therapeutic potential of buprenorphine-inspired compounds for inhibiting opioid-assoicated abuse liability and physical dependence and assess its functional effecitvenss and selectivity. Our unique set of behavioral and physiological assays in awake, behaving non-human primates, in combination with the availability of novel buprenorphine-inspired compounds, sets the breakthrough stage for the identification of an effective medication for opioid-induced adverse effects and sheds light on future clinical interventions and the treatment options for opioid use disorder.