Optimization of triaryl bis-sulfones as cannabinoid-2 receptor ligands

Characterizing Cannabinoid CB2 Receptor Ligands Using DiscoveRx PathHunter™ β-Arrestin Assay

“…5 We are particularly interested in a class of triaryl bis sulfone inverse agonists specific for the human cannabinoid CB 2 receptor. 6 We have found that these compounds display a biology not easily explained by classic pharmacology (see Discussion section). Because of these observations, and our desire to assess the value of novel G-protein-coupled receptor (GPCR)-based assay platforms for high-throughput library screening campaigns, we have evaluated a select set of cannabinoid compounds including several triaryl bis sulfones for activation of the cannabinoid CB 2 receptor using the DiscoveRx Pathhunter of interest and β-arrestin.…”

Synthesis of Novel Cannabinoid Ligands and Their Use as Anti-Glioma and Anti-Inflammatory Agents

“…162 j. Triaryl bis-sulfones. 163 These compounds act via the CB1 or CB2 receptors (and possibly GPR55) and are agonists, antagonists, inverse agonists, or partial agonist/antagonists. They are collectively known as "cannabimimetic" agents, "cannabinergic" agents, or simply "cannabinoids."…”

Functional Activity and Switching of Novel Cannabinergic Ligands

“…The primary example being the trifluoromethyl derivative (186 Figure 5.5) (CB2 Ki = 2.9 nM; CB1 Ki/CB2 Ki = 4403) exhibited similar selectivity ratios, but o-F-phenyl demonstrated a superior CB2 Ki. 335 With a newly optimized C-ring, the amide moiety of the A-ring was re-examined, and data demonstrated that a trifluromethylsulfonamide (190, Figure 5.5) (CB2 Ki = 2 nM) held top honors. 335 The next step in optimization of the compound was to examine the halogen substitution on the B-ring; however, Cl held its place atop the possible moieties examined.…”

“…335 With a newly optimized C-ring, the amide moiety of the A-ring was re-examined, and data demonstrated that a trifluromethylsulfonamide (190, Figure 5.5) (CB2 Ki = 2 nM) held top honors. 335 The next step in optimization of the compound was to examine the halogen substitution on the B-ring; however, Cl held its place atop the possible moieties examined. 335 To complete the cycle, the C-ring was examined with the newly optimized trifluoromethylsulfonamide present on the A-ring, and as with the Cl, o-F-phenyl retained its spot.…”

“…335 The next step in optimization of the compound was to examine the halogen substitution on the B-ring; however, Cl held its place atop the possible moieties examined. 335 To complete the cycle, the C-ring was examined with the newly optimized trifluoromethylsulfonamide present on the A-ring, and as with the Cl, o-F-phenyl retained its spot. …”