Novel 1′,1′-Chain Substituted Hexahydrocannabinols: 9β-Hydroxy-3-(1-hexyl-cyclobut-1-yl)-hexahydrocannabinol (AM2389) a Highly Potent Cannabinoid Receptor 1 (CB1) Agonist

What is it about?

In pursuit of a more detailed understanding of the structural requirements for the key side chain cannabinoid pharmacophore,we have extended our SARto cover a variety of conformationallymodified 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 C10 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 C10 position leads to an optimal affinity and selectivity interaction with CB1. Thus, two of the C10-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.

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