The long-term goals of the proposed research are to develop efficient asymmetric synthesis of C-11 functionalized delta-9 THC derivatives. The synthetic methodology to be developed will be general enough to be applied to naturally occuring cannabinoids, the family of human metabolites and analogs. To date there is no stereospecific method for the efficient synthesis of C-11 functionalized cannabinoids of the delta-9 series. The proposed research will provide a reliable route to these compounds through the application of a unique cyclization reaction which has been recently discovered, and by choosing a highly suitable terpene fragment to combine with an olivetol derivative. The terpene fragment is cheap, available in high optical purity (both enantiomers are in fact available), and it lends itself to chemical modification. Cannabinoids exert a variety of useful physiological effects: analgesic, antiemetic, anticonvulsant, treatment of glaucoma, and others. They have potential for use in the treatment of opiate withdrawal symptoms. There are currently several cannabinoid analogs in clinical use. Since it has recently been shown that cannabinoids exert their physiological effects at the receptor level, it is important to develop syntheses which are suitable for the preparation of radiolabelled compounds. The tools of choice for in vivo studies of the pharmacology and metabolism of drugs are PET and SPECT, therefore the rapid introduction of a short-lived positron emitter in the last stage of the chemical synthesis is required. The development of synthesis which are suitable for this application places the greatest demands on the organic chemist. The proposed syntheses are ideal for such applications. Furthermore, this research will be deployed for the preparation of conformationally restricted variants of the cannabinoids. Such compounds may have enhanced activity or may act as a cannabinoid antagonist.

R01DA006731

1990-09-30

1994-08-31