title: Synthesis and anticonvulsant evaluation of dimethylethanolamine analogues of valproic acid and its tetramethylcyclopropyl analogue.
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.
  
  
  CONCLUSIONS
  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.
authors: Institute of Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Israel.
authors: Tawfeeq
authors: T
authors: Shekh-Ahmad
authors: Meir
authors: M
authors: Bialer
authors: Eylon
authors: E
authors: Yavin
mesh_terms: D000818:Animals; D000927:Anticonvulsants / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D058256:Brain Waves / Q000187:drug effects; D003292:Convulsants / Q000633:toxicity; D003521:Cyclopropanes / Q000493:pharmacokinetics; D003642:Deanol / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004569:Electroencephalography; D004597:Electroshock / Q000009:adverse effects; D004827:Epilepsy / Q000097:blood / Q000139:chemically induced / Q000188:drug therapy* / Q000209:etiology; D006624:Hippocampus / Q000187:drug effects / Q000503:physiopathology; D007696:Kindling, Neurologic / Q000187:drug effects; D008297:Male; D051379:Mice; D010433:Pentylenetetrazole / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D014635:Valproic Acid / Q000031:analogs & derivatives
chemical_list: D000927:Anticonvulsants; D003292:Convulsants; D003521:Cyclopropanes; C033650:2,2,3,3-tetramethylcyclopropanecarboxylic acid; D003642:Deanol; D014635:Valproic Acid; D010433:Pentylenetetrazole