title: Hashish: synthesis and central nervous system activity of some novel analogues of cannabidiol and oxepin derivatives of delta 9-tetrahydrocannabinol.
abstract: Several C-10 substituted cannabidiol (CBD) derivatives and novel oxepin derivatives of delta 9-tetrahydrocannabinol (delta 9-THC) were synthesized and evaluated for biological activity in mice and dogs. Treatment of 10-bromocannabidiol diacetate (3) with various amines in Me2SO gave the corresponding 10-aminocannabidiol derivatives 4-6. Similarly, treatment of 3 with NaN3 gave the azido compound 7, which with LiA1H4 afforded the 10-aminocannabidiol 9. However, reduction of 7 with CrCl2 formed the amide 8, which on further reduction with LiA1H4 gave the N-ethyl analogue 10. Coupling of 9 with 11 in the presence of dicyclohexylcarbodiimide formed 12, which was then deprotected with HCl to give the analogue 13. The oxepin analogue 14a was synthesized from 3 by treatment with Na2CO3 in CH3OH/H2O at room temperature. The dimethylheptyl analogue 14b was similarly prepared. Incorporation of N-ethyl (10), N-methyl-N-propargyl (6), and morpholino (4) groups in CBD at position 10 resulted in analogues that were more potent than CBD in producing hypoactivity in mice. These analogues had relatively little effect on rectal temperature. Selected substitutions at C-10 also resulted in analogues that were partially effective in blocking delta 9-THC antinociceptive activity. This blockade was observed particularly in compound 10, which also showed unusually toxic properties. Incorporation of a seven-membered oxepin in the delta 9-THC structure eliminated cannabinoid activity although substitution of the pentyl side chain with a 1,2-dimethylheptyl in the oxepin 14b resulted in CNS depression in mice.
authors.forename: V S
authors.initials: VS
authors.lastname: Jorapur
authors.forename: Z H
authors.initials: ZH
authors.lastname: Khalil
authors.forename: R P
authors.initials: RP
authors.lastname: Duffley
authors.forename: R K
authors.initials: RK
authors.lastname: Razdan
authors.forename: B R
authors.initials: BR
authors.lastname: Martin
authors.forename: L S
authors.initials: LS
authors.lastname: Harris
authors.forename: W L
authors.initials: WL
authors.lastname: Dewey
mesh_terms: D000700:Analgesics / Q000494:pharmacology; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002185:Cannabidiol / Q000031:analogs & derivatives; D002490:Central Nervous System / Q000187:drug effects*; D004285:Dogs; D013759:Dronabinol / Q000031:analogs & derivatives*; D005260:Female; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D010082:Oxepins / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000700:Analgesics; D010082:Oxepins; D002185:Cannabidiol; D013759:Dronabinol