New Resorcinol-Anandamide "Hybrids" as Potent Cannabinoid Receptor Ligands Endowed with Antinociceptive Activity in Vivo

Bearing in mind the pharmacophoric requirements of both (-)-trans-Delta(9)-tetrahydrocannabinol (THC) and anandamide (AEA), we designed a novel pharmacophore consisting of both a rigid aromatic backbone and a flexible chain with the aim to develop a series of stable and potent ligands of cannabinoid receptors. In this paper we report the synthesis, docking studies, and structure-activity relationships of new resorcinol-anandamide "hybrids" differing in the side chain group. Compounds bearing a 2-methyloctan-2-yl group at position 5 showed a significantly higher affinity for cannabinoid (CB) receptors, in particular when an alkyloxy chain of 7 or 10 carbon atoms was also present at position 1. Derivative 32 was a potent CB(1) and CB(2) ligand, with K(i) values similar to that of WIN 55-212 and potent antinociceptive activity in vivo. Moreover, derivative 38, although less potent, proved to be the most selective ligand for CB, receptor (K(i)(CB(1)) = 1 mu M, K(i)(CB(2)) = 35 nM).