Synthesis and pharmacological evaluation of amino, azido, and nitrogen mustard analogues of 10-substituted cannabidiol and 11- or 12-substituted delta 8-tetrahydrocannabinol.
The synthesis of a variety of novel 10-substituted cannabidiol (CBD) and 11- or 12-substituted delta 8-tetrahydrocannabinol (delta 8-THC) analogues containing amino, alkylamino, azido, or a N,N-bis(2-chloroethyl)amino functional group is described, as well as their pharmacological evaluation in mice. These analogues, which possess only a portion of the full pharmacological spectrum of activity of delta 9-THC, indicate that cannabinoid-mediated reduction of spontaneous locomotor activity, hypothermia, antinociception, and/or catalepsy need not be produced simultaneously, possibly suggesting the existence of more than one mechanism of action. The 10-substituted CBD analogues 3, 4, and 5 with an ethylamino, propylamino, or azido functional group, respectively, proved to be largely inactive, except for the production of central nervous system (CNS) depression concomitant with toxicity. Toxicity and CNS depression may be related phenomena in these nitrogenous compounds since 12-amino and 12-ethylamino analogues (8 and 11) of delta 8-THC also proved to be very toxic. Antinociceptive and hypothermic responses (without reduction of motor activity) were observed at a dose of 10 mg/kg of the 11-ethylamino analogue (9) of delta 8-THC, while a dose of 50 mg/kg of the nitrogen mustard 11-[N,N-bis(2-chloroethyl)amino]-delta 8-THC (12) was necessary to produce any observable pharmacological effect. When selected analogues were evaluated for antagonistic properties, they failed to attenuate the effects of delta 9-THC. Some nitrogen mustard analogues were capable of producing minimal pharmacological effects after either peripheral or direct CNS administration; however, these analogues also failed to attenuate the effects of delta 9-THC either immediately after administration or 24-48 h later.
Compton
D R
DR
Medical College of Virginia, Virginia Commonwealth University, Richmond 23298.
Little
P J
PJ
Martin
B R
BR
Gilman
J W
JW
Saha
J K
JK
Jorapur
V S
VS
Sard
H P
HP
Razdan
R K
RK
D000700:Analgesics / Q000138:chemical synthesis*; D000818:Animals; D002185:Cannabidiol / Q000031:analogs & derivatives* / Q000633:toxicity; D002186:Cannabinoids; D055598:Chemical Phenomena; D002621:Chemistry; D004305:Dose-Response Relationship, Drug; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000633:toxicity; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D012119:Respiration / Q000187:drug effects; D013329:Structure-Activity Relationship
D000700:Analgesics; D002186:Cannabinoids; D002185:Cannabidiol; D013759:Dronabinol