Jamal Zahalka’s research while affiliated with Hebrew University of Jerusalem and other places

The cannabimimetic activity of the two enantiomers of 11-hydroxy-delta-8-tetrahydrocannabinol (11-OH-delta-8-THC) was evaluated in pigeons trained to discriminate between the presence and absence of (-)-delta-9-tetrahydrocannabinol [(-)-delta-9-THC]. (-)-11-OH-Delta-8-THC exhibited cannabimimetic activity with a potency (ED50, 0.17 mg/kg) similar to that of delta-9-THC. The duration of action for (-)-11-OH-delta-8-THC was shorter than that observed for delta-9-THC. No cannabimimetic activity was seen after administrations of (+)-11-OH-delta-8-THC, indicating enantiomeric selectivity for the discriminable effects. A dose-related decrease in response rate occurred with (-)-11-OH-delta-8-THC, but not with (+)-11-OH-delta-8-THC; the latter compound produced an increase in responding at 3 mg/kg. Open-field behavior in Mongolian gerbils indicated marked suppression of rearing (vertical activity) after treatments with (-)-delta-9-THC and (-)-11-OH-delta-8-THC; this did not occur after (+)-11-OH-delta-8-THC. The results support the notion of cannabimimetic enantiospecificity.

The separation of six pairs of chiral cannabinoids was achieved using a dimethylphenylcarbamate derivative of amylose, immobilized on silica gel (ChiralPak AD, Daicel), using 2-propanol and ethanol as the modifiers of n-hexane in the mobile phase. Good separation was achieved for most of the solutes in both solvent systems under various conditions. The chromatographic parameters of various cannabinoids in the two solvent systems were determined. The pairs differ from each other in small structural features such as the degree of saturation, position of a double bond and closure of a pyran ring. Therefore, a comparative study could give some clues regarding the mechanism of discrimination between the enantiomeric pairs on the chiral stationary phase. Preliminary measurements of limit of determination showed that it was possible to assess 99.9% enantiomeric purity of the cannabinoids, owing to the high efficiency of the separation. Enantiomers of two monoterpenes, used as intermediates or as starting materials in the chiral synthesis of cannabinoids, were also separated, hence the described procedure is capable of assessing whether the chiral centres in the molecules were sustained throughout the synthetic procedures.

The present overview covers various aspects of research going on in the Cannabis field in the Department of Natural Products at the Hebrew University. In the first part we discuss, and try to explain, the reason for the absence of the term Cannabis (and possibly also opium) in the Old Testament. In the second part we bring evidence that, contrary to widely held views, stereospecificity of cannabinoid action is extremely high, and in certain cases almost absolute. Previous results seem to have been due to impurities in the samples tested. (+)-Delta-1-THC, (+)-delta-6-THC and (+)-7-hydroxy-delta-6-THC, when purified sufficiently, exhibit activity of about 1% of that of the natural (-) enantiomers. A new labelled cannabinoid ligand has been prepared by catalytic reduction of (-)-7-hydroxy-delta-6-THC dimethylheptyl. The equatorial C-1 epimer obtained binds to the cannabinoid receptor with a KI of 40 pM. This compound is one of the most active cannabinoids tested so far for binding to the canabinoid receptor, and may become an important tool in cannabinoid research.

The individual enantiomers of the 1,1-dimethylheptyl homolog of 7-hydroxy- Δ6-tetrahydrocannabinol, (1) and (2a), which exhibit distinct pharmacological profiles, have beenobtained with very high e.e. by synthesis from the antipodes of myrtenol.

The 1,1-dimethylheptyl tetrahydrocannabinol derivative (+)-(V) as well as its enantiomer (-)-(V) are prepared with high optical purities (> 99.8%) starting from both enantiomers of myrtenol (I).