ABSTRACT
BACKGROUND: Valproic acid (VPA) is a major antiepileptic drug (AED) that is less potent than other AEDs. 2,2,3,3-Tetramethylcyclopropanecarboxylic acid (TMCA) is an inactive cyclopropyl analogue of VPA that serves as a starting material for the synthesis of CNS-active compounds. METHODS: New conjugation products between N,N'-dimethylethanolamine to VPA and TMCA to form N,N-dimethylethanolamine valproate (DEVA) and N,N-dimethylethanolamine 2,2,3,3-tetramethylcyclopropionate were synthesized and their anticonvulsant activity was assessed in the maximal electroshock seizure (MES) and subcutaneous metrazol (scMet) seizure tests and the hippocampal kindling model in mice and/or rats. An amide analogue of DEVA (DEVAMIDE) was also synthesized and evaluated. The pharmacokinetics of DEVA and DEVAMIDE was comparatively evaluated in rats. RESULTS: In rats DEVA acted as a prodrug of VPA and had ED(50) values of 73 mg/kg and 158 mg/kg in the MES and the hippocampal kindling models, respectively. At these two anticonvulsant models DEVA was seven-times more potent than VPA. DEVAMIDE was active in the MES test at doses of 100 mg/kg (mice) and its rat-MES-ED(50)=38.6 mg/kg however, its protective index (PI=TD(50)/ED(50)) was twice lower than DEVA's PI. The TMCA analogues were inactive at the mice MES and scMet models. DEVA underwent rapid metabolic hydrolysis to VPA and consequently, in its pharmacokinetic analysis only VPA plasma levels were monitored. In contrast, DEVAMIDE was stable in whole blood. CONCLUSION: DEVA acts in rats as a prodrug of VPA yet shows a more potent anticonvulsant activity than VPA. DEVAMIDE acted as the drug on its own and was more potent than DEVA at the rat-MES test.
Subject(s)
Anticonvulsants/chemical synthesis , Anticonvulsants/therapeutic use , Deanol/chemical synthesis , Deanol/therapeutic use , Epilepsy/drug therapy , Animals , Anticonvulsants/blood , Anticonvulsants/chemistry , Brain Waves/drug effects , Convulsants/toxicity , Cyclopropanes/pharmacokinetics , Deanol/blood , Deanol/chemistry , Disease Models, Animal , Electroencephalography , Electroshock/adverse effects , Epilepsy/blood , Epilepsy/chemically induced , Epilepsy/etiology , Hippocampus/drug effects , Hippocampus/physiopathology , Kindling, Neurologic/drug effects , Male , Mice , Pentylenetetrazole/toxicity , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Valproic Acid/analogs & derivativesABSTRACT
Effects of retro-inverso (RI) modifications of HTLV-1 protease inhibitors containing a hydroxyethylamine isoster backbone were clarified. Construction of the isoster backbone was achieved by a stereoselective aldol reaction. Four diastereomers with different configurations at the isoster hydroxyl site and the scissile site substituent were synthesized. Inhibitory activities of the new inhibitors suggest that partially modified RI inhibitors would interact with HTLV-1 protease in the same manner as the parent hydroxyethylamine inhibitor.
Subject(s)
Aspartic Acid Endopeptidases/antagonists & inhibitors , Deanol/analogs & derivatives , Deanol/chemical synthesis , Deanol/pharmacology , Protease Inhibitors/chemical synthesis , Protease Inhibitors/pharmacology , Aspartic Acid Endopeptidases/genetics , Dose-Response Relationship, Drug , Human T-lymphotropic virus 1/drug effects , Human T-lymphotropic virus 1/genetics , Indicators and Reagents , Mutation , Structure-Activity RelationshipABSTRACT
Modified series of phosphorusless edelfosine analogues bearing the polar heads of aliphatic bases, N,N-dimethylethanolamine and N,N,N(1),N(1)-tetramethylethylenediamine, were synthesized, with the length of the spacer varying from three to four methylene units. The cytotoxic characteristics of the compounds synthesized were studied.