Development of agonists, partial agonists and antagonists in the Delta(8)-tetrahydrocannabinol series

Synthetic sequences were developed (Schemes 1 to 6) for the syntheses of va rious Delta(8)-THC analogs with either a rigid acetylenic linkage or a cis- double bond in different positions in the side chain. Various alkyne and ci s-ene-Delta(8)-THC analogs were also synthesized carrying a functional grou p such as a cyano, isothiocyano, azido, amino, nitro, bromo, hydroxy, fluor o and a methoxy group at the chain terminal. The in vitro and in vivo pharm acology of these unique analogs have provided several ligands which are par tial agonists or antagonists of the cannabinoid receptor CB1. The 2'-positi on in the side chain was found to be optimum for activity. (C) 1999 Elsevie r Science Ltd. All rights reserved.