Potent cyano and carboxamido side-chain analogues of 1', 1'-dimethyl-delta8-tetrahydrocannabinol.
The synthesis and pharmacological profile of several cyano (1a-e) and carboxamido (2a-h) side-chain-substituted analogues of 1', 1'-dimethyl-Delta8-THC are described. Commercially available cyano compound 3 was transformed to the resorcinol 6 in a three-step sequence. Condensation of 6 with p-menth-2-ene-1,8-diol formed the THC 7a which, with sodium cyanide/DMSO, gave 1b. Protection of the phenol in 7a as the MOM derivative provided the common intermediate 8 for the synthesis of 1a,c,e. Compound 1d was also synthesized from 7a via the aldehyde 9a. Base hydrolysis of 1b gave the acid 10 which, via its acid chloride and subsequent treatment with the appropriate amine, formed the target compounds 2a-h. The pharmacological profile indicated that the cyano analogues 1a-e had very high CB1 binding affinity (0.36-13 nM) and high in vivo potency as agonists. Two analogues (1a,b) had extremely high potency in the mouse tetrad tests. The dimethylcarboxamido analogue 2a showed a similar profile to 1a,b. The high potency was also retained in analogue 2c. In contrast the sulfonamide analogue 2d was unique as it had greater affinity than Delta9-THC, yet it was practically devoid of agonist effects. This study suggests that the incorporation of a cyano or an amide substituent in the side chain of Delta8-THC-DMH can enhance potency and can also lead to compounds with a unique profile which have high binding affinity and are practically devoid of agonist effects.
Organix, Inc., 240 Salem Street, Woburn, Massachusetts 01801, USA.
M
M
Singer
W J
WJ
Ryan
B
B
Saha
B R
BR
Martin
R K
RK
Razdan
D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D002186:Cannabinoids / Q000737:chemistry / Q000378:metabolism; D013759:Dronabinol / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018476:Hypokinesia / Q000139:chemically induced / Q000503:physiopathology; D007035:Hypothermia / Q000139:chemically induced / Q000503:physiopathology; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010147:Pain Measurement; D011869:Radioligand Assay; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000819:agonists / Q000378:metabolism; D013329:Structure-Activity Relationship
D002186:Cannabinoids; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; D013759:Dronabinol