Enantioselective synthesis of 1-methoxy- and 1-deoxy-2'-methyl-delta8-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)-delta8-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)-delta8-THC (JWH-359), (2'S)-1-deoxy-3-(2'-methylbutyl)-delta8-THC (JWH-352), (2'S)-1-deoxy-3-(2'-methylpentyl)-delta8-THC (JWH-255), and (2'R)-1-deoxy-3-(2'-methylpentyl)-delta8-THC (JWH-255), have good affinity (K(i) = 13-47 nM) for the CB2 receptor and little affinity (K(i) = 1493 to >10,000 nM) for the CB1 receptor. In the 1-deoxy-3-(2'-methylalkyl)-delta8-THC series, the 2'S-methyl compounds in general have greater affinity for the CB2 receptor than the corresponding 2'R isomers.
Huffman
John W
JW
Howard L. Hunter Laboratory, Clemson University, Clemson, SC 29634-0973, USA. huffman@clemson.edu
Bushell
Simon M
SM
Joshi
Sudhir N
SN
Wiley
Jenny L
JL
Martin
Billy R
BR
D013759:Dronabinol / Q000138:chemical synthesis* / Q000494:pharmacology*; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D043885:Receptor, Cannabinoid, CB2 / Q000187:drug effects*; D021241:Spectrometry, Mass, Electrospray Ionization; D013237:Stereoisomerism
D008024:Ligands; D043885:Receptor, Cannabinoid, CB2; D013759:Dronabinol