Evaluation of the enantioselective antiallodynic and pharmacokinetic profile of propylisopropylacetamide, a chiral isomer of valproic acid amide

Dan Kaufmann, Boris Yagen, Anne Minert, Michael Tal, Marshall Devor, Meir Bialer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Propylisopropylacetamide (PID) is a chiral CNS-active constitutional isomer of valpromide, the amide derivative of the major antiepileptic drug valproic acid (VPA). The purpose of this work was: a) To evaluate enantiospecific activity of PID on tactile allodynia in the Chung (spinal nerve ligation, SNL) model of neuropathic pain in rats; b) To evaluate possible sedation at effective antiallodynic doses, using the rotorod ataxia test; c) To investigate enantioselectivity in the pharmacokinetics of (R)- and (S)-PID in comparison to (R,S)-PID; and d) To determine electrophysiologically whether PID has the potential to affect tactile allodynia by suppressing ectopic afferent discharge in the peripheral nervous system (PNS). (R)-, (S)- and (R,S)-PID produced dose-related reversal of tactile allodynia with ED50 values of 46, 48, 42 mg/kg, respectively. The individual PID enantiomers were not enantioselective in their antiallodynic activity. No sedative side-effects were observed at these doses. Following i.p. administration of the individual enantiomers, (S)-PID had lower clearance (CL) and volume of distribution (V) and a shorter half-life (t1/2) than (R)-PID. However following administration of (R,S)-PID, both enantiomers had similar CL and V, but (R)-PID had a longer t1/2. Systemic administration of (R,S)-PID at antiallodynic doses did not suppress spontaneous ectopic afferent discharge generated in the injured peripheral nerve, suggesting that its antiallodynic action is exerted in the CNS rather than the PNS. Both of PID's enantiomers, and the racemate, are more potent antiallodynic agents than VPA and have similar potency to gabapentin. Consequently, they have the potential to become new drugs for treating neuropathic pain.

Original languageAmerican English
Pages (from-to)699-707
Number of pages9
JournalNeuropharmacology
Volume54
Issue number4
DOIs
StatePublished - Mar 2008

Keywords

  • Enantioselective pharmacokinetics
  • Neuropathic pain
  • Pharmacodynamics
  • Propylisopropylacetamide enantiomers
  • Spinal nerve ligation
  • Valproic acid

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