Novel sulfenamides and sulfonamides based on pyridazinone and pyridazine scaffolds as CB 1 receptor ligand antagonists

Abstract A series of sulfenamide and sulfonamide derivatives was synthesized and evaluated for the affinity at CB 1 and CB 2 receptors. The N -bornyl- S -(5,6-di- p -tolylpyridazin-3-yl)-sulfenamide, compound 11 , displayed good affinity and high selectivity for CB 1 receptors ( K i values of 44.6 nM for CB 1 receptors and >40 μM for CB 2 receptors, respectively). The N- isopinocampheyl-sulfenamide 12 and its sulfonamide analogue 22 showed similar selectivity for CB 1 receptors with K i values of 75.5 and 73.2 nM, respectively. These novel compounds behave as antagonists/inverse agonists at CB 1 receptor in the [ 35 S]-GTPγS binding assays, and none showed adequate predictive blood–brain barrier permeation, exhibiting low estimated LD 50 . However, testing compound 12 in a supraspinal analgesic test (hot-plate) revealed that it was as effective as the classic CB 1 receptor antagonist rimonabant, in reversing the analgesic effect of a cannabinoid agonist.