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Purpose: Amino acid esters containing tertiary or quaternary nitrogen heterocycles were synthesized for dexanabinol (1) and evaluated as water-soluble prodrugs or congeners., Methods: Syntheses were performed by conventional methods; stability studies in water, blood (rat, dog, human) and assay-media were performed by HPLC; NMDA receptor binding was determined by [3H] MK-801 displacement; neuroprotection and neurotoxicity studies were performed in cortical cell cultures., Results: 7-morpholino and N-methylpiperazino acetates and butyrates and the respective N-methylmorpholinium and piperazinium iodides as well as a 3'-N-methyl morpholino butyrate and the corresponding N-methyl quaternary type derivative were synthesized. All compounds were relatively soluble in water or 10% aqueous ethanol. The examined derivatives were stable in water and generally less stable in blood and assay media. Quaternary derivatives of dexanabinol were found to hydrolyze faster. All examined compounds inhibited NMDA receptor and protected neurons against NMDA induced toxicity. Neuroprotection (with one exception) is however attributed to the parent 1 released by hydrolysis during the assay., Conclusions: Some of the examined derivatives could be further evaluated as prodrugs on congeners of 1.

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 pro-drug candidates for 1; the glycinate ester 3 might be used as an active analog.

45Ca accumulation was studied autoradiographically as a marker for lethally injured brain tissue following closed head injury (CHI), and applied to an investigation of the neuroprotective effect of the non-psychoactive cannabinoid (+)-(3S,4S)-7-hydroxy-D-6 tetrahydro-cannabinol 1,1-dimethylheptyl (HU-211). Amassment of 45Ca in rat brain was examined 24 or 72 h after induction of CHI in the left hemisphere by a weight-drop device. Concentration of 45Ca within 15 different brain regions was assessed by relative optical density. There was increased 45Ca accumulation in the hemisphere ipsilateral to the side of the insult as compared with the contralateral hemisphere. The highest density of radioactive labeling was found in the anterior cortex and in the frontal parts of the parietal cortex, with accumulation expanding as a function of time post injury. On the third day following trauma the amount of accumulated 45Ca was higher than that at 24 h after CHI, with more distant 45Ca-accumulating structures involved: the ventral posterolateral nucleus of the thalamus and the substantia nigra. Histological examination revealed necrotic tissue in the regions accumulating 45Ca. HU-211, a stereoselective inhibitor of the N-methyl-D-aspartate (NMDA) receptor, was injected immediately after induction of trauma. One day after trauma, HU-211 had significantly decreased both the volume of the 45Ca accumulating zone and the concentration of the amassed radioisotope. In the HU-211 treated rats a considerable reduction in radioactive labeling was also found 72 h after trauma. The ability of HU-211 to decrease 45Ca accumulation after head trauma is probably due to its ability to attenuate Ca2+ fluxes through the NMDA receptor-mediated calcium channels and to reduce the depolarization evoked Ca2+ fluxes. On the basis of our results, HU-211 seems to be a promising therapeutic agent for head trauma in humans.