Novel sulfenamides and sulfonamides based on pyridazinone and pyridazine scaffolds as CB1 receptor ligand antagonists

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