Structure-based Optimization of Novel Analgesics without Reinforcing Liabilities

Opioid drugs like morphinecodeineand fentanyl have conferred life saving analgesia for million enabling medical interventions impossible without themThese benefits are off set by dose limiting liabilitieslike respiratory depression and toleranceand by addictionThe dangers of opioids have received wideattentionas many Americans die from overdoses as from gunshot wounds and car accidentscombinedMany opioid side effects are mediated not by the canonical G protein pathway of theopioid receptorbut by arrestin based signalingThis has inspired a decade long search for mu opioid receptor agonists thatactivate Gi but not arrestinbiased signalingleading to drugs like oliceridineIt also led to the discovery ofPZMa novel scaffoldusing structure based discoveryPZMis a Gi biased mu agonist that confersanalgesia without respiratory depression and without reinforcing activityHere we have two goalsDeveloping analogs with improved drug like propertiesandTestingthese analogs for analgesiafor respiratory depressionand for reinforcing liabilitiesThe specific aims areAimStructure based improvement of drug like propertiesPZMhas remarkable signalingpropertiesbut it has not been optimized for pharmacokineticsUsing structure guided medicinal chemistrywewill optimize analogs for drug like properties that will move the series toward IND enablementMilestonesWe will design and synthesize analogs thatIimprove oral bio availabilityIIReduceclearance and increase metabolic stabilityIIIIncrease CNS permeabilityAll the while we will test for andretain the potencymu opioid biased agonism and potentially kappa opioid antagonism of PZMAimTesting PZManalogs in rodents for efficacy and liabilitiesPZMs reduced respiratorydepression and lack of reinforcing behavior conditioned place preference assays are encouragingImprovedPK will help us understand how these behaviors relate to signaling as a prequel to true addiction assaysMilestonesIn rat studieswe willITest the new analogs for analgesia in heatcoldand mechanosensitivity assaysthe goal is to leverage the improved PK emerging from Aimto achieve higher analgesia atlower dosesIITest the new analogs for respiratory depressionseeking analogs that maintain PZMs lackof respiratory depressionIIITest the analogs for reinforcement in conditioned place preference assaysheretoothe goal is better analgesia without reinforcementA broad goal is to develop an SAR relating in vitrosignaling to analgesiarespiratory effectsand reinforcing behaviorPZMis a novel chemotype with unique biologythese studies will advance the family it representstowards IND enablement as a potential solution to the mounting opioid overdose epidemic Public Health RelevanceOpioid drugs like morphinecodeineand fentanyl have conferred life saving analgesia formillionsenabling medical interventions impossible without themThese benefits are off set bydose limiting liabilitieslike respiratory depression and toleranceand by addictionThe goal ofthis project is to discover new opioid like drugs that will have reduced liabilitiesultimatelyreducing deaths from these essential drugs