Comparative pharmacodynamic and pharmacokinetic analysis of two anticonvulsant halo derivatives of 2,2,3,3-tetramethylcyclopropanecarboxamide, an amide of a cyclic analog of valproic acid.
OBJECTIVE
α-Fluoro-2,2,3,3-tetramethylcyclopropanecarboxamide (α-F-TMCD) and α-Cl-TMCD, are α-halo derivatives of TMCD, the corresponding amide of a cyclopropane analog of valproic acid (VPA). This study aimed to comparatively evaluate the pharmacodynamics and pharmacokinetics of α-F-TMCD and α-Cl-TMCD in rodent models of epilepsy and for antiepileptic drug (AED)-induced teratogenicity. The potential of α-F-TMCD as an antiallodynic and antinociceptive compound was also evaluated.


METHODS
α-F-TMCD and α-Cl-TMCD were synthesized. α-Cl-TMCD anticonvulsant activity was evaluated in comparison to VPA in the mouse maximal-electroshock-seizure (MES), Metrazol (scMet), and 6-Hz psychomotor-seizure tests. Neurotoxicity was assessed by the Rotorod-ataxia test. Induction of neural tube defects (NTDs) by α-Cl-TMCD and α-F-TMCD was evaluated after intraperitoneal administration to a mouse strain highly susceptible to VPA-induced teratogenicity. The ability of α-F-TMCD to reduce pain was evaluated in the rat spinal nerve ligation (SNL) model for neuropathic pain and in the formalin test. α-F-TMCD and α-Cl-TMCD pharmacokinetics was evaluated following intraperitoneal (40 mg/kg) and oral (60 mg/kg) administration to rats.


RESULTS
α-F-TMCD and α-Cl-TMCD had similar potencies in the 6-Hz test and were more potent than VPA in this model and in the scMet test. Neither induced NTDs, and both exhibited wide safety margins. α-F-TMCD was active in the two pain models, and was found to be equipotent to gabapentin in the SNL model (ED(50) = 37 and 32 mg/kg, respectively). Comparative pharmacokinetic analysis showed that α-Cl-TMCD is less susceptible to liver first-pass effect than α-F-TMCD because of lower total (metabolic) clearance and liver extraction ratio.


CONCLUSIONS
Based on their potent anticonvulsant activity and lack of teratogenicity, α-F-TMCD and α-Cl-TMCD have the potential for development as new antiepileptics and central nervous system (CNS) drugs.
Pessah
Neta
N
Institute for Drug Research, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Kaufmann
Dan
D
Yagen
Boris
B
Hen
Naama
N
Wlodarczyk
Bogdan
B
Finnell
Richard H
RH
Bialer
Meir
M
D000014:Abnormalities, Drug-Induced / Q000209:etiology / Q000517:prevention & control; D000577:Amides / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D000700:Analgesics / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000927:Anticonvulsants / Q000493:pharmacokinetics* / Q000494:pharmacology*; D003521:Cyclopropanes / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000494:pharmacology*; D004195:Disease Models, Animal; D004827:Epilepsy / Q000517:prevention & control*; D006801:Humans; D051379:Mice; D009436:Neural Tube Defects / Q000139:chemically induced / Q000517:prevention & control; D010146:Pain / Q000517:prevention & control; D010433:Pentylenetetrazole / Q000494:pharmacology; D051381:Rats; D014635:Valproic Acid / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000494:pharmacology
C116673:2,2,3,3-tetramethylcyclopropane carboxamide; D000577:Amides; D000700:Analgesics; D000927:Anticonvulsants; D003521:Cyclopropanes; D014635:Valproic Acid; D010433:Pentylenetetrazole