Our goal is to develop an innovative pharmacotherapy for cannabis use disorder (CUD) that affects over 4 millionAmericans. We propose to develop a novel second generation PARTIAL inverse agonist of the cannabinoid 1receptor (CB1) that has a benign behavioral profile for CUD. Cannabinoids are the second most abused class ofdrug in the world and there is no FDA approved medication for CUD -- making this an area of urgent need. Thepsychoactive effects of cannabis and synthetic cannabinoids result from activation of central CB1 receptors.Blocking the rewarding and craving properties of drugs of abuse is a well-validated and accepted strategy forsubstance use disorders (SUD) without a strong adverse physical withdrawal component. Rimonabant is a potentFULL inverse agonist of the CB1 receptor that was approved in Europe as an anti-obesity agent. Unfortunately,rimonabant produced adverse dysphoric effects in ~6% of users -- effects likely due to sustained high brainexposure and potent inverse agonism, which led to its eventual discontinuation. In human studies, rimonabantwas efficacious in treating many aspects of CUD. Artiam Bio is developing the next generation of CB1 antagoniststhat are expected to have a superior adverse effect profile compared to rimonabant and previous clinicalcandidates. Artiam Bio's lead compound is an orally active, potent, and selective CB1 partial inverse agonist withlimited brain penetration. This compound is functionally as efficacious as rimonabant but produces nodysphoria/anhedonia in rodent studies. Further development of this compound is proposed through three aims.Through aim 1, ~500 g of the compound will be synthesized using an established chemical route leveraging uponArtiam's experience with a congener. Through aims 2 and 3, dose range finding toxicological studies will beperformed in two species and toxicokinetic parameters will be established. Successful completion of this phase 1SBIR application will pave the way for GLP regulatory studies and other IND-enabling activities of Artiam's leadcandidate for CUD.
Public Health Relevance Statement: Project Narrative
Our goal is to develop a special class of compounds that only partially blocks signaling through the receptor
that is targeted by marijuana and related products. This will lead to a new drug to treat addiction to cannabis
products.
Project Terms: | <9-ene-Tetrahydrocannabinol><Î(1)-THC><Î(1)-tetrahydrocannabinol><Î(9)-THC><Î(9)-tetrahydrocannabinol><Î-9-tetrahydrocannabinol><Î9-tetrahydrocannabinol>
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