Evaluation of the enantioselective antiallodynic and pharmacokinetic profile of propylisopropylacetamide, a chiral isomer of valproic acid amide.
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 ED(50) 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 (t(1/2)) than (R)-PID. However following administration of (R,S)-PID, both enantiomers had similar CL and V, but (R)-PID had a longer t(1/2). 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.
Kaufmann
Dan
D
Department of Pharmaceutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel.
Yagen
Boris
B
Minert
Anne
A
Tal
Michael
M
Devor
Marshall
M
Bialer
Meir
M
D000502:Allylisopropylacetamide / Q000031:analogs & derivatives* / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use; D000700:Analgesics / Q000493:pharmacokinetics* / Q000627:therapeutic use; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use; D019540:Area Under Curve; D017763:Autonomic Denervation / Q000379:methods; D004195:Disease Models, Animal; D004341:Drug Evaluation; D006930:Hyperalgesia / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D009437:Neuralgia / Q000150:complications / Q000188:drug therapy / Q000378:metabolism*; D010147:Pain Measurement / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013997:Time Factors
D000700:Analgesics; D000927:Anticonvulsants; D000502:Allylisopropylacetamide; C009072:propylisopropylacetamide