I. It is generally considered that the natural (3R,4R) Delta1- tetrahydrocannabinol (Delta1-THC) is only about 13-20 times more active than the synthetic (3S,4S) enantiomer. On the basis of preliminary work we consider that the stereospecificity of THC activity is, in actuality, absolute. We plan to prepare stereochemically pure enantiomers and test them in the mouse ring test and by drug discrimination techniques. II. We plan to prepare two new types of cannabinoid probes (labelled with tritium on the methyl group of cyclohexene ring and on one of the methyl groups of the pyran ring). We shall use these probes for the identification of possible new subgroups of the cannabinoid receptor. III. Little is known on the antiemetic SAR of cannabinoids. We plan to test for antiemetic activity in pigeons various natural and synthetic cannabinoids in order to establish SAR rules. On the basis of preliminary work we expect to be able to show that separation can be achieved between cannabimimetic and antiemetic activity. IV. Work by our group and that of S. Burstein has shown that separation between cannabimimetic and analgetic activity is possible. We plan to prepare compounds, mainly of two types (cannabinoid- 7-oic acids and monoalkyl ethers of cannabidiol type of compounds) for which preliminary indications exists for separation of activity. V. We have shown that (+)-7-OH-Delta6-THC dimethylhepty homolog (HU-211) blocks respiratory depression by morphine. We plan to expand our research in this area and to look for similar blocking of opiate activity in analgesia and gastrointestinal activity.
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