P 3: PSYCHOACTIVITY OF CANNABINOIDS & INTERACT W/ DELTA-9-TETRAHYDROCANNABINOL

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Twenty four compounds have been isolated from Cannabis extracts using a combination of different chromatographic techniques, including vaccum liquid chromatography, open column chromatography, and HPLC (normal and reversed phase). The structures of the isolated compounds were established by UV, IR, GC-MS, HR-ESI-MS, 1D and 2D- NMR experiments. Nine out of the 24 identified compounds were isolated for the first time from Cannabis. These nine compounds include four hydroxylated cannabinoids, epoxycannabigerolic acid, three tetrahydrocannabinoic acid esters, and one THC aldehyde. The remaining 14 compounds are known and include 11 cannabinoids: dehydrocannabifuran, cannabicitran, cannabicyclol, cannabicyclolic acid, cannabigerol, cannabigerolic acid, cannabinol, cannabinolic acid, THC acid A, THC, and cannabiripsol; 3 non-cannabinoid phenolics: cannabispiran I, cannabispiranol, and canniflavin B; and one sterol: beta-sitosterol. All of the isolated compounds were subjected to CB1 receptor affinity assays (primary screen). Only four compounds showed highly significant inhibition in the assays, highly comparable with that of THC, and one showed moderate inhibition. The five active compounds are hydroxylated cannabinoids and four of them are new natural products. The IC50s of the active compounds are 589 nM, 624 nM, 73 nM, 1256 nM and 6408 nM. These compounds were subjected to GTP¿S assays in order to determine if they are agonists or antagonists.