Prediction and Experimental Confirmation of NovelPeripheral Cannabinoid‑1 Receptor Antagonists

Small molecules targeting peripheral CB1 receptors have therapeutic potential in a variety of disorders including obesity-related, hormonal and metabolic abnormalities, while avoiding the psychoactive effects in the CNS. We applied our in house algorithm, Iterative Stochastic Elimination, to produce a ligand-based model that distinguishes between CB1R antagonists and random molecules, by physico-chemical properties only. We screened ~2 million commercially available molecules, and found that about 500 of them are potential candidates to antagonize CB1R. We applied a few criteria for peripheral activity and narrowed that set down to 30 molecules, out of which 15 could be purchased. Ten out of those 15 showed good affinity to CB1R and two of them with nanomolar affinities (Ki of ~400 nM). The eight molecules with top affinities were tested for activity: two compounds are pure antagonists, and five others are inverse agonists. These molecules are now being examined in vivo for their peripheral vs. central di...