A NOVEL APPROACH FOR PAIN TREATMENT WITHOUT OPIOID LIABILITIES

DESCRIPTION provided by applicant Every year about million adult Americans experience some form of pain a condition that costs the nation between $ billion and $ billion annually in lost productivity and treatment The recently released `National Pain Strategyandapos developed by the NINDSandapos s IPRCC recognizes acute and chronic pain as a serious and costly public health issue and articulates that new treatment approaches need to be developed to reduce the burden of pain in the US Opioid analgesics are the mainstay of pain treatment and often the only treatment option that provides significant relief However opioid analgesics which are mainly mu opioid receptor MOP agonists are controlled substances that have abuse potential and are riddled with other side effects such as constipation nausea and tolerance which impede their long term safety and effectiveness There is clearly a need for new analgesics that provide opioid like efficacies without the liabilities of opioid pain killers he nociceptin opioid receptor NOP the th member of the opioid receptor family and its endogenous peptide ligand nociceptin orphanin FQ N OFQ are emerging new targets for pain medications The NOP receptor and N OFQ are found throughout in pain processing pathways in the brain and spinal cord and modulate opioid function by blocking opioid reward and even tolerance We and others have shown that the natural peptide N OFQ and small molecule NOP agonists and bifunctionalandapos NOP agonists with mu opioid agonist activity show potent analgesic effects on acute and chronic pain are non rewarding and do not develop tolerance These findings suggest that NOP receptor agonists may be an attractive approach to obtain potent analgesic efficacies without opioid related liabilities In our Phase I project we investigated th analgesic potential of NOP agonists in a transgenic mouse model of `sickle cell diseaseandapos SCD which develops spontaneous hyperalgesia similar to the condition in sickle patients SCD is associated with severe pain which remains a major challenge to treat Opioids are the current standard of care but due to side effects and development of tolerance remain a sub optimal approach to treat SCD pain particularly when needed on a continued basis Development of effective analgesics devoid of opioid liabilities would have a significant impact on pain treatment in SCD Our Phase I studies showed that the NOP agonist mu low efficacy agonist AT showed significant antinociceptive efficacy in sickle mice more potent and longer lasting than high dose morphine AT also showed a sustained analgesic effect without tolerance development These promising data that NOP agonists and or NOP mu bifunctional agonists are promising analgesics for treating chronic pain such as sickle pain In this Phase II project we propose to conduct lead optimization and medicinal chemistry to identify novel NOP targeted `preclinical lead candidatesandapos which are optimized for their drug like suitability and novelty hav in vivo efficacy in pain models in rodents and nonhuman primates and preliminary evaluation of toxicity that are ready to be advanced into IND enabling studies for development as pain medications PUBLIC HEALTH RELEVANCE This application proposes early translational studies of lead optimization and efficacy confirmation to develop `preclinical lead candidatesandapos as a novel class of analgesics that have potent opioid like analgesia but without opioid liabilities of constipation tolerance and abuse liability Successful completion of these studies will validate a new approach for the treatment of chronic and severe acute pain and importantly result in preclinical drug candidates that are ready to be advanced into IND enabling studies for development as novel pain medications