Synthesis and pharmacology of a hybrid cannabinoid

A pentacyclic hybrid cannabinoid (4) has been synthesized, which combines s tructural elements of traditional cannabinoids and cannabmimetic indoles. C annabinoid 4 contains a 1-pentylindole structure fused to the 2,3-positions of the partially reduced hydroxydibenzopyran system of THC. The successful approach to 4 employed 9-benzoyl-5,7-dimethoxy-1,2,3,4-tetrahydrocarbazole (17) as the starting material. Dehydrogenation to carbazole 18, followed b y demethylation and condensation with trans-p-menthadienol gave N-benzoyl h ybrid cannabinoid 22, N-alkylation of which afforded target cannabinoid 4. The hybrid cannabinoid had affinity for the CB1 receptor approximately equa l to that of Delta(8)-THC (K-i=19.3+/-3 nM), and shows comparable potency i n vivo. (C) 2000 Elsevier Science Ltd. All rights reserved.