Stereochemical Requirements for Cannabimimetic Activity

About 15 years ago, we formulated some tentative rules for cannabimimetic structure-activity relationships (SAR) (Edery et al. 1971 Mecboulam and Edery 1973). These rules were based on work our group had done since 1964, when we isolated and elucidated the structure of delta-1-tetrahydrocannabinol (delta-1-THC) (Gaoni and Mechoulam 1964), as well as on research by numerous other groups. Most of our work was done with rhesus monkeys much of the work by the other groups was done with either rodents or dogs. However, gratifyingly, the results obtained with different species were qualitatively comparable. 

Most of the rules have withstood the erosion of time, although exceptions have been noted and certain refinements have to be made. 

The aromatic hydroxyl group has to he free or esterified. Blocking of the hydroxyl group as an ether inactivates the molecule. It is possible that the esters are actually inactive but undergo hydrolysis in vivo to the free phenols. Thus, delta-1-THC acetate, when tested in vitro, shows negligible activity in biochemical reactions in which delta-1-THC is active (Baneijee et al. 1975). 

An all carbon side chain on C-5 is not an absolute requirement. The side chain may contain an etheric oxygen (e.g., compound 3) (Loev et al. 1973). 

7-Hydroxy THCs, which are major metabolites, are very potent cannabimimetics. Monohydroxylation on other position of the terpene ring also usually leads to active derivatives. Dihydroxylation generally causes loss of activity. Further oxidation of the C-7 hydroxyl group to a carboxyl group causes inactivation. 

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Mechoulam, R. Lander, N. Srebnik, M. Breuer, A. Segal, M. Feigenbaum, J.J. Jarbe, T.U.C. Consroe, P. Stereochemical Requirements for Cannabimimetic Activity in Structure-Activity Relationships of the Cannab-inoids NIDA Research Monograph Series 79. 

Mechoulam R, Lander N, Srebnik M, Breuer A, Segal M, Feigenbaum JJ, Jarbe TU, Consroe P (1987) Stereochemical requirements for cannabimimetic activity. NIDA Res Monogr 79 15-30... 

Another aspect of the stereochemical requirements for cannabinoid activity is the need for enantiomeric purity. The natural A -THC and A6-THC are (3R,4R) isomers [101]. The synthetic route which was developed by our laboratory for A -THC and A6-THC nearly 20 years ago [ 102] makes possible also the synthesis of the (35,45) enantiomers (+ )-verbenol on condensation with olivetol leads to (29), which on ring opening leads to (+ )-(35,45)-A6-THC (30), which can be converted with ease into (+ )-(35,45)-A -THC (31) (Scheme 5.1). In several tests for cannabimimetic activity, ( + )-A -THC (31) was ca. 13-20-times less active than the (- )-isomer [72, 103]. These results indicate pharmacologic enantiomeric preference rather than absolute stereo-... 

The SAR of cannabimimetic activity in the cannabinoid series are reviewed with emphasis on the stereochemical requirements. Some new results are presented. The most important are that a, in humans, (-)-(lS)-delta-3-THC is much more active than (+)-( R)-delta-3-THC and b, with the 7-OH-delta-6-THC DMH enantiomers (32) and (33), the activity in several animal species resides completely in the (-)-(3R, 4R) enantiomer (32). The difference between the two enantiomers being up to several thousand times. The (3R,4R)-enantiomer (32) is much more active than delta-1- or delta-6-THC in animal tests, the exact level of activity depending on the test employed. The cannabimimetically inactive (+)-(3S,4S) enantiomer (33) was shown to be a potent analgetic in several animal tests. Thus, a complete dissociation between the cannabimimetic and the analgetic effects in a cannabinoid has been achieved, apparently for the first time. 

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