Enantioselective synthesis of 1-methoxy- and 1-deoxy-2′-methyl-Δ8-tetrahydrocannabinols: New selective ligands for the CB2 receptor

Two new series of cannabinoids were prepared and their affinities for the CB1 and CB2 receptors were determined. These series are the (2′R)- and (2′S)-1-methoxy- and 1-deoxy-3-(2′-methylalkyl)-Δ8-tetrahydrocannabinols, with alkyl side chains of three to seven carbon atoms. These compounds were prepared by a route that employed the enantioselective synthesis of the resorcinol precursors to the cannabinoid ring system. All of these compounds have greater affinity for the CB2 receptor than the CB1 receptor and four of them, (2′R)-1-methoxy-3-(2′-methylbutyl)-Δ8-THC (JWH-359), (2′S)-1-deoxy-3-(2′-methylbutyl)-Δ8-THC (JWH-352), (2′S)-1-deoxy-3-(2′-methylpentyl)-Δ8-THC (JWH-255), and (2′R)-1-deoxy-3-(2′-methylpentyl)-Δ8-THC (JWH-255), have good affinity (Ki = 13–47 nM) for the CB2 receptor and little affinity (Ki = 1493 to >10,000 nM) for the CB1 receptor. In the 1-deoxy-3-(2′-methylalkyl)-Δ8-THC series, the 2′S-methyl compounds in general have greater affinity for the CB2 receptor than the corresponding 2′R isomers.

The enantioselective synthesis and pharmacology of two series of (2′R)- and (2′S)-methyl-Δ8-THC ligands are described. R = H, OCH3; R′ = methyl to n-pentyl.Figure optionsDownload as PowerPoint slide