DERIVATIVES OF DEXANABINOL .1. 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 o r congeners. Methods. Conventional procedures were used for the synthe sis of the novel derivatives. Stability studies in water and blood (ra t, dog, human) were performed by HPLC; NMDA receptor binding was deter mined by radio ligand [H-3] MK-801-displacement; the neuroprotection a nd neurotoxicity studies were performed in cortical cell cultures. Res ults. Glycinate (3), dimethyl- and diethylamine (5, 6), trimethyl- and triethyl- ammonium (7, 8) acetates of 1 were synthesized. All compoun ds were relatively soluble and stable in water. The quaternary ammoniu m salt-type derivatives rapidly hydrolyzed to the parent drug in vario us 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 derivativ es were associated with very low neuronal cell toxicity and are credit ed to parent compound released by hydrolysis during the experiments ra ther than to intrinsic activity. Conclusions. Compounds 7 and 8 are pr omising water-soluble prodrug candidates for 1 the glycinate ester 3 m ight be used as an active analog.