DERIVATIVES OF DEXANABINOL .2. 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 wat er-soluble prodrugs or congeners. Methods: Syntheses were performed by conventional methods; stability studies in water, blood (rat, dog, hu man) and assay-media were: performed by HPLC; NMDA receptor binding wa s determined by [H-3] MK-801 displacement; neuroprotection and neuroto xicity studies were performed in cortical cell cultures. Results: M-mo rpholino and N-methylpiperazino acetates and butyrates and the respect ive N-methylmorpholinium and piperazinium iodides as well as a 3'-N-me thyl morpholino butyrate and the corresponding N-methyl quaternary typ e derivative were synthesized. All compounds were relatively soluble i n water or 10% aqueous ethanol. The examined derivatives were stable i n water and generally less stable in blood and assay media. Quaternary derivatives of dexanabinol were found to hydrolyze faster. All examin ed compounds inhibited NMDA receptor and protected neurons against NMD A induced toxicity. Neuroprotection (with one exception) is however at tributed to the parent 1 released by hydrolysis during the assay. Conc lusions: Some of the examined derivatives could be further evaluated a s prodrugs on congeners of 1.