文摘
In pursuit of a more detailed understanding of the structural requirements for the key side chain cannabinoid pharmacophore, we have extended our SAR to cover a variety of conformationally modified side chains within the 9-keto and 9-hydroxyl tricyclic structures. Of the compounds described here, those with a seven-atom long side chain substituted with a cyclopentyl ring at C1′ position have very high affinities for both CB1 and CB2 (0.97 nM < Ki < 5.25 nM), with no preference for either of the two receptors. However, presence of the smaller cyclobutyl group at the C1′ position leads to an optimal affinity and selectivity interaction with CB1. Thus, two of the C1′-cyclobutyl analogues, namely, (6aR,10aR)-3-(1-hexyl-cyclobut-1-yl)-6,6a,7,8,10,10a-hexahydro-1-hydroxy-6,6-dimethyl-9H-dibenzo[b,d]pyran-9-one and (6aR,9R,10aR)-3-(1-hexyl-cyclobut-1-yl)-6a,7,8,9,10,10a-hexahydro-6,6-dimethyl-6H-dibenzo[b,d]pyran-1,9 diol (7e-β, AM2389), exhibited remarkably high affinities (0.84 and 0.16 nM, respectively) and significant selectivities (16- and 26-fold, respectively) for CB1. Compound 7e-β was found to exhibit exceptionally high in vitro and in vivo potency with a relatively long duration of action.