Cannabimimetic activity of novel enantiomeric, benzofuran cannabinoids.
The synthesis of the (2R,3R,4S,6R)-7/(2S,3S,4R,6S)-8 enantiomeric pair of benzofuran cannabinoids is reported together with the 1H and 13C NMR spectral parameters. In benzofuran 8 the configurational arrangement of ligated groups at the stereogenic C(3) atom (through which the terpene moiety is connected to the aromatic ring) is very similar to that of the corresponding atom in natural (3R,4R)-delta 1-tetrahydrocannabinol (delta 1-THC), although their respective Cahn-Ingold-Prelog descriptors are different. In drug-discrimination tests in pigeons and rats, benzofuran 8 is as active as delta 1-THC; in the mouse ring test compound 8 is more active than delta 6-THC. Enantiomer 7 is considerably less active than enantiomer 8 in both tests. These results can be explained by the fact that both 7 and 8 have a dimethylheptyl side chain (which is known to enhance cannabimimetic activity) and that delta 1-THC and benzofuran 8 have closely related conformations, as determined by molecular mechanics.
Mechoulam
R
R
School of Pharmacy, Hebrew University, Jerusalem, Israel.
Breuer
A
A
Järbe
T U
TU
Hiltunen
A J
AJ
Glaser
R
R
D000818:Animals; D001572:Benzofurans / Q000138:chemical synthesis* / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D002186:Cannabinoids / Q000138:chemical synthesis* / Q000494:pharmacology; D010856:Columbidae; D013759:Dronabinol / Q000494:pharmacology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D051381:Rats; D011919:Rats, Inbred Strains; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001572:Benzofurans; D001578:Benzopyrans; D002186:Cannabinoids; D013759:Dronabinol