Medications for Synthetic Cannabinoid Abuse

PROJECT SUMMARY ABSTRACT In response to PAthis Phase I STTR proposal will aim at developing pharmacotherapies that can act aslife savermedications to counteract the neurotoxic effects of synthetic cannabinoidsSCsTowards this goalwe will synthesize CB R antagonists with fast onsets of action that can be administered in an emergency roomERsituationThe rationale is based on the successful soft agonist controlled deactivation approach developed at the Northeastern University sNEUCenter for Drug DiscoveryCDDThe newly discovered ligands will be devoid of the undesirable effects caused by known CBinverse agonists due to their ability to undergo rapid deactivation into inactive metabolitesGiven that patientsdrug histories may not be known at admissiona key desired characteristic of the proposed antagonists as compared to the well studied CBinverse agonist rimonabantSRis that they do not induce prolonged withdrawal reactionsFirst generation SCs act as full CB R agonistsmimic themarijuana higheffects oftetrahydrocannabinolTHCand exert their psychotropic effects with increased CBpotency via CB R activationSCs are illegally sold asdesigner drugsand their consumption can be fatal unlikeTHC which is a partial agonist and is less toxicLatelythere has been a dramatic increase in SC related visits to emergency rooms and calls to poison control centers across the USAAimwill focus on the design and synthesis of novel controlled deactivation CB R antagonists by utilizing the human CB RhCBcrystal structure that was recently determined by our groupThe design encompasses prototypes that have helped establish proof of conceptAimwill focus on the in vitro characterization of ligands to determine their hCBaffinityhCBhCBselectivityfunctional behaviorand stabilityAimwill focus on identifying brain penetrant compounds wherein ligands will be tested for CBantagonism and for their side effects using procedures that are highly reproducible in mice of both gendersFulfilling Phase I goals will further establish proof of concept for providing such treatment and for identifying advanced druggable leadsThe project will help transition the most successful compounds towards Phase II for further optimization and pre clinical evaluation aimed at obtaining one candidate andback upsThe next phase of this grant will focus on testing the optimized leads in validated pre clinical rodent models of SC induced neurotoxicity using established behavioral paradigms that are considered perfect translational models to humansPhase II III development of the most favorable compounds will aim towards IND enabling studies while partnering with industry PROJECT NARRATIVE The goal of this Phase I STTR proposal is to develop novel controlled deactivation medications displaying fast on sets that can block attenuate and rapidly normalize the neurotoxic effects of synthetic cannabinoidsSCsand can be used during an emergency responseThe new ligands will be devoid of side effects of known CBinverse agonistse grimonabantPhase II studies should allow for further lead optimizationside effect profiling and preclinical studies that will be directed towards IND enablement