The biaryl cannabinoid mimetic reported by Gareau, et al. (Bioorg Med Chem Lett 6:189, 1996), and shown by us to have potent antihyperalgesic activity in the Freund’s complete adjuvant-induced hyperalgesia assay in the rat (Stabley, et al. Program No. 578.9. Abstract Viewer/Itinerary Planner SfN, 2003), is a valuable lead compound to explore the structure activity relationships at the human cannabinoid CB1 and CB2 receptors. The biaryl lead compound, although being nonselective in its binding profile and its activation of the hCB receptors, provided a starting point for the synthesis of new analogs with substitutions on the top aryl ring. We tested these analogs for their ability to inhibit [3H]CP55940 binding to cloned human CB1 and CB2 receptors expressed in Chinese hamster ovary cells, as well as for their abilities to stimulate [35S]GTPγS binding mediated by these receptors. Binding affinities of the analogs ranged from ca. 1.0 nM to > 1000 nM without dramatic divergence in the SAR profiles for the two...