POTENT CYANO AND CARBOXAMIDO SIDE-CHAIN ANALOGS OF 1',1'-DIMETHYL-DELTA(8)-TETRAHYDROCANNABINOL

The synthesis and pharmacological profile of several cyano (1a-e) and carboxamido (2a-h) side-chain-substituted analogues of 1',1'-dimethyl- Delta(8)-THC are described. Commercially available cyano compound 3 wa s transformed to the resorcinol 6 in a three-step sequence. Condensati on of 6 with p-menth-2-ene-1,8-diol formed the THC 7a which, with sodi um cyanide/ DMSO, gave Ib. Protection of the phenol in 7a as the MOM d erivative 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 su bsequent treatment with the appropriate amine, formed the target compo unds 2a-h. The pharmacological profile indicated that the cyano analog ues 1a-e had very high CB1 binding affinity (0.36-13 nM) and high in v ivo potency as agonists. Two analogues (1a,b) had extremely high poten cy in the mouse tetrad tests. The dimethylcarboxamido analogue 2a show ed a similar profile to 1a,b. The high potency was also retained in an alogue 2c. In contrast the sulfonamide analogue 2d was unique as it ha d greater affinity than Delta(9)-THC, yet it was practically devoid of agonist effects. This study suggests that the incorporation of a cyan o or an amide substituent in the side chain of Delta(8)-THC-DMH can en hance potency and can also lead to compounds with a unique profile whi ch have high binding affinity and are practically devoid of agonist ef fects.