Further Branching of Valproate-Related Carboxylic Acids Reduces the Teratogenic Activity, but Not the Anticonvulsant Effect

Abstract

In the present study, compounds derived from the anticonvulsant drug valproic acid (VPA, 2-n-propylpentanoic acid) and analogues known to be teratogenic were synthesized with an additional carbon-branching in one of the side chains. The substances were tested for their ability to induce anticonvulsant activity and sedation in adult mice, and neural tube defects (exencephaly) in the offspring of pregnant animals (Han:NMRI mice). In all cases, the rates of exencephaly, embryolethality, and fetal weight retardation induced by the methyl-branched derivatives were very low when compared to those of the parent compounds. These novel compounds exhibited anticonvulsant activity which was not significantly different from that of VPA. Neurotoxicity was considerably lower for some compounds as compared to VPA. Anticonvulsant activity and neurotoxicity of branched short chain fatty acids are far less structure-dependent and not related to teratogenic potency. Within this series of compounds, (+/-)-4-methyl-2-n-propyl-4-pentenoic acid and (+/-)2-isobutyl-4-pentenoic acid exhibited the most favorable profile in regard to high anticonvulsant effect, low sedation, and teratogenicity. Valproic acid analogues with additional methyl branching may be valuable antiepileptic agents with low teratogenic potential.

Modulation of Peroxisome Proliferator-Activated Receptor δ Activity Affects Neural Cell Adhesion Molecule and Polysialyltransferase ST8SiaIV Induction by Teratogenic Valproic Acid Analogs in F9 Cell Differentiation

“…The teratogenic potency of VPA and its analogs has previously been determined in vivo (Nau et al, 1991;Hauck and Nau, 1992;Bojic et al, 1996Bojic et al, , 1998. The structural elements previously shown to be essential for teratogenicity have been confirmed by the results of the expression of NCAM and PST1: the molecule has to bear a carboxylic group, and the carbon atom adjacent to the carboxylic group has to have one hydrogen atom (Ehlers et al, 1992).…”

“…E-2-en-VPA was obtained from Desitin (Hamburg, Germany). The other VPA derivatives and the pure enantiomers (R)-and (S)-4-yn-VPA were synthesized as described by Hauck and Nau (1992) and Bojic et al (1996).…”

“…It has been shown that the teratogenic effects are caused by VPA itself, not one of its metabolites (Ehlers et al, 1992). The teratogenic effects in vivo and in vitro depend on structural requirements (Nau et al, 1991;Bojic et al, 1996;Lampen et al, 1999). In vitro only teratogenic VPA derivatives induce cell differentiation of embryonic F9 stem cells (Lampen et al, 1999), which is believed to reflect early events in the embryonal development (Alonso et al, 1991;Werling et al, 2001), whereas nonteratogenic VPA derivatives did not induce F9 cell differentiation.…”

Valproic Acid Antagonizes the Capacity of Other Histone Deacetylase Inhibitors To Activate the Epstein-Barr Virus Lytic Cycle

“…Further studies have demonstrated that the teratogenic effects of NaB and TSA are tightly correlated with their activities as HDAC inhibitors (29). However, the anticonvulsant properties of VPA are not linked to HDAC inhibition (9,29). These studies demonstrate that VPA has properties distinct from those of other HDAC inhibitors.…”

Novel valproic acid derivatives with hemoglobin F inducing activity

“…VPA derivatives were synthesized as described before [7][8][9]. Determination of HbF synthesis was performed using a specific ELISA [5].…”