In contrast to VPD which is biotransformed to VPA, the aforementioned cyclopropane derivatives were found to be stable to amide-acid biotransformation. TMCD and M-TMCD show that cyclic analogues of VPD, like its aliphatic isomers, must have either two substitutions at the beta position to the carbonyl, such as in the case of TMCD, or a substitution in the alpha and in the beta positions like in the VPD isomer, valnoctamide (VCD). This paper discusses the antiepileptic potential of tetramethylcyclopropane analogues of VPD which are in animal models more potent than VPA and may be non-teratogenic and non-hepatotoxic.
GABA is a major inhibitory neurotransmitter in mammals, whose uptake in glial cells is inhibited by nipecotic acid. In addition to GABA, glycine is an important inhibitory neurotransmitter. Valproic acid (VPA) is one of the four established antiepileptics and (E)‐2‐ene valproic acid ( (E)‐2‐ene VPA) is its major active metabolite. The described structure–pharmacokinetic–pharmacodynamic relationship (SPPR) study explored the possiblity of utilizing valproyl derivatives of glycine and nipecotic acid as new antiepileptics. The pharmacokinetics and pharmacodynamics (anticonvulsant activity and neurotoxicity) of the following conjugation products were investigated: (E)‐2‐ene valproyl glycinamide (between (E)‐2‐ene VPA and glycinamide) and valproyl nipecotic acid and valproyl nipecotamide (between VPA and nipecotic acid). Out of the investigated compounds only (E)‐2‐ene valproyl glycinamide showed a good anticonvulsant profile in both mice and rats due to its better pharmacokinetic and pharmacodynamic profile. (E)‐2‐ene valproyl glycinamide was more potent than VPA and showed an activity and a safety margin similar to those of its analogous compound valproyl glycinamide. The investigated valproyl derivatives did not operate as chemical drug delivery systems (CDDSs) of glycine or nipecotic acid, but, rather, acted as drugs on their own. (E)‐2‐ene valproyl glycinamide was partially excreted unchanged in the urine (fe=7·4%), while its urinary metabolite was (E)‐2‐ene valproyl glycine. Unlike the new antiepileptic tiagabine, in which nipecotic acid is attached to 4, 4‐di‐(3‐methylthien‐2‐yl)‐3‐butenyl and yields an active compound, the conjugation between nipecotic acid or its amide and VPA yielded inactive entities. In contrast to nipecotic acid, the conjugation between VPA or (E)‐2‐ene VPA and glycinamide gave two active compounds with similar pharmacokinetic and pharmacodynamic profiles.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.