Fixed dose analgesic combination with non-opioid mechanism to prevent opioid misuse

PROJECT SUMMARYABSTRACTWith nearlymln people suffering from chronic pain in the US alone and the global market projected to reach $bln bythere is both a major unmet medical need and a significant commercial opportunityDominated by opioid drugsthis field also suffered from alarming consequences of opioid drug overuse and misuseAntagonists acting at TRPVreceptor have long been recognized as one of the most promising novel classes of non opioid analgesicsSeveral drug companies have developed highly selective and potent compoundsInitial tests in humans have confirmed pharmacodynamic profile expected for this class of agentsi eanalgesiaHoweverdespite an overall good safety and tolerabilitythere were significant effects on thermoregulation resulting in clinically meaningful hyperthermia and partial loss of heat sensitivityThese effects have led to the discontinuation of essentially all of the advanced programs in the field of TRPVantagonistsIn this regardand in line with funding opportunity RFA DAthe current application proposes to conduct a set of preclinical proof of concept studies in rats to support the claims thatat doses that have minimalclinically acceptable or negligible impact on cardiovascular functionaadrenoceptor agonists can diminish thermoregulatory effects of TRPVreceptor antagonistsIn Phasewe will demonstrate thatAimpresynaptically acting aadrenoceptor agonists such as lofexidine can prevent or diminish the hyperthermic responses to TRPVreceptor antagonistsAimat the doses controlling thermoregulatory effects of TRPVreceptor antagonistsaadrenoceptor agonists have minimal or acceptable effects on hypotension PROJECT NARRATIVE In an effort to combat overuse and misuse of opioid analgesicswe propose an agent with the different mechanismAntagonists acting at the TRPVreceptors have long been recognized as one of the most promising novel classes of non opioid analgesics but adverse effects on thermoregulation have led to the discontinuation of essentially all of the advanced programs in the field of TRPVantagonistsSynventa has discovered a method of controlling the unwanted thermoregulatory effects of TRPVantagonists by combining them with centrally acting aadrenoceptor agonistsLed by experienced drug huntersa PI with medicinal chemistry background and a pharmacologistSynventa proposes to conduct a set of preclinical proof of concept studies to support the claims thatat doses that have minimalclinically acceptable or negligible impact on cardiovascular functionaadrenoceptor agonists can diminish thermoregulatory effects of TRPVreceptor antagonists