Subject(s)
Gaucher Disease/drug therapy , Glucosylceramidase/administration & dosage , Absorption , Drug Carriers , Drug Delivery Systems , Enzyme Stability , Feasibility Studies , Glucosylceramidase/therapeutic use , Humans , Lipids/chemistry , Liposomes/chemistry , Serum Albumin/chemistry , Serum Albumin/pharmacologyABSTRACT
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.
Subject(s)
Dronabinol/analogs & derivatives , Excitatory Amino Acid Antagonists/chemistry , Morpholines/chemistry , Neuroprotective Agents/chemistry , Piperazines/chemistry , Animals , Binding, Competitive , Cells, Cultured , Dizocilpine Maleate/metabolism , Dizocilpine Maleate/pharmacology , Dogs , Dronabinol/blood , Dronabinol/chemistry , Dronabinol/pharmacology , Drug Stability , Excitatory Amino Acid Antagonists/chemical synthesis , Excitatory Amino Acid Antagonists/pharmacology , Humans , Hydrolysis , Morpholines/chemical synthesis , Morpholines/pharmacology , Nervous System Diseases/chemically induced , Neurons/drug effects , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/pharmacology , Piperazines/chemical synthesis , Piperazines/pharmacology , Prodrugs/chemical synthesis , Prodrugs/chemistry , Prodrugs/metabolism , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/metabolism , Solubility , Structure-Activity Relationship , Tritium , Water/chemistryABSTRACT
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.
