Antiepileptic drugs (AEDs) are often utilized in the treatment of
neuropathic pain. The major AED
valproic acid (VPA) is of particular interest as it is thought to engage a variety of different neural mechanisms simultaneously. However, the clinical use of VPA is limited by two rare but life-threatening side effects: teratogenicity and hepatotoxicity. We synthesized VPA's corresponding
amide:
valpromide (VPD), two of VPAs isomers and their corresponding
amides;
valnoctic acid (VCA),
valnoctamide (VCD), diisopropyl
acetic acid (
DIA), diisopropylacetamide (DID), and VPD's congener: N-methyl-VPD (MVPD). VCD, DID and VPD are nonteratogenic, potentially nonhepatotoxic, and exhibit better anticonvuslant potency than VPA. In this study, we assessed the antiallodynic activity of these compounds in comparison to VPA and
gabapentin (GBP) using the rat spinal nerve
ligation model of
neuropathic pain (SNL, Chung model). VCA and MVPD were inactive. However, VPD (20-100 mg kg(- 1)), VCD (20-100 mg kg(- 1)) and DID (20-90 mg kg(- 1)) produced dose-related reversal of
tactile allodynia with ED50 values of 61, 52 and 58 mgkg(- 1), respectively. All the
amides were more potent than VPA (ED50=269 mgkg(- 1)). The antiallodynic effect of VPA, VPD, VCD and DID was obtained at plasma concentrations of 125, 24, 18 and 7 mg l(- 1), respectively, with a good pharmacokinetic-pharmacodynamic correlation and a minimal lag response. VCD and DID were found to have minimal motor and
sedative side effects at
analgesic doses, and were equipotent to GBP, currently the leading
drug in
neuropathic pain treatment. Consequently, VCD and DID have potential to become new drugs for the treatment of
neuropathic pain.