A-834,735

full agonist at both the CB₁ and CB₂ receptors, with a K_i of 12 nM at CB₁ and 0.21 nM at CB₂. Replacing the aromatic 3-benzoyl or 3-naphthoyl group found in most indole derived cannabinoids with the 3-tetramethylcyclopropylmethanone group of A-834,735 and related compounds imparts significant selectivity for CB₂, with most compounds from this group found to be highly selective CB₂ agonists with little affinity for CB₁. However, low nanomolar CB₁ binding affinity is retained with certain heterocyclic 1-position substituents such as (N-methylpiperidin-2-yl)methyl (cf. AM-1220, AM-1248), or the (tetrahydropyran-4-yl)methyl substituent of A-834,735, resulting in compounds that still show significant affinity and efficacy at both receptors despite being CB₂ selective overall.^{[1][2][3][4][5]}