Derivatives of dexanabinol. II. Salts of amino acid esters containing tertiary and quaternary heterocyclic nitrogen with increased water-solubility

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.