Derivatives of dexanabinol. I. Water-soluble salts of glycinate esters

Purpose. Glycinate ester-type water soluble derivatives of dexanabinol (HU-211) (1) a non-psychotropic cannabinoid with potential use in the treatment of brain damage were synthesized and evaluated as prodrugs or congeners. Methods. Conventional procedures were used for the synthesis of the novel derivatives. Stability studies in water and blood (rat, dog, human) were performed by HPLC; NMDA receptor binding was determined by radio ligand [³H]MK-801-displacement; the neuroprotection and neurotoxicity studies were performed in cortical cell cultures. Results. Glycinate (3), dimethyl- and diethylamine (5, 6), trimethyl- and triethyl- ammonium (7, 8) acetates of 1 were synthesized. All compounds were relatively soluble and stable in water. The quaternary ammonium salt-type derivatives rapidly hydrolyzed to the parent drug in various types of blood including human. In vitro activity studies indicated that the novel derivatives possess NMDA receptor binding properties. The neuroprotecting properties manifested by some of the new derivatives were associated with very low neuronal cell toxicity and are credited to parent compound released by hydrolysis during the experiments rather than to intrinsic activity. Conclusions. Compounds 7 and 8 are promising water-soluble prodrug candidates for 1; the glycinate ester 3 might be used as an active analog.