Studies on the teratogen pharmacophore of valproic acid analogues: evidence of interactions at a hydrophobic centre

Bojic, Ursula; Ehlers, Katharine; Ellerbeck, Ursula; Bacon, Christopher L.; O'Driscoll, E.; O'Connell, Cormac; Berezin, Vladimir; Kawa, Anna; Lepekhin, Eugene A.; Bock, Elisabeth; Regan, Ciaran M.; Nau, Heinz

doi:10.1016/s0014-2999(98)00462-2

Cited by 58 publications

(69 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Even at these high concentrations that were maternally toxic, M-TMCD and TMCD did not appear to induce NTDs, indicating that these compounds will not induce NTDs at therapeutic concentrations. The results of this study are in agreement with the previously reported structural requirements of a VPA analogue to induce NTDs (31,32). It should be emphasized that all frontline AEDs do have teratogenic effects in humans and experimental animals, and therefore it is important to identify new anticonvulsant compounds that may not be teratogenic.…”

Section: Discussionsupporting

confidence: 91%

“…As a result of a series of structure-teratogenicity relation studies, a hypothetical binding site for VPA and related analogues, for the VPAinduced NTDs have been proposed (31). This binding site involves an electronic interaction site, ionic interaction or H-bonding site, and a hydrophobic pocket (32). M-TMCD is a cyclopropyl amide derivative of VPA and an analogue of VPD.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Anticonvulsant Profile and Teratogenicity of N‐methyl‐tetramethylcyclopropyl Carboxamide: A New Antiepileptic Drug

et al. 2002

View full text Add to dashboard Cite

Summary: Purpose:The studies presented here represent our efforts to investigate the anticonvulsant activity of N-methyltetramethylcyclopropyl carboxamide (M-TMCD) and its metabolite tetramethylcyclopropyl carboxamide (TMCD) in various animal (rodent) models of human epilepsy, and to evaluate their ability to induce neural tube defects (NTDs) and neurotoxicity.Methods: The anticonvulsant activity of M-TMCD and TMCD was determined after intraperitoneal (i.p.) administration to CF#1 mice, and either oral or i.p. administration to Sprague-Dawley rats. The ability of M-TMCD and TMCD to block electrical-, chemical-, or sensory-induced seizures was examined in eight animal models of epilepsy. The plasma and brain concentrations of M-TMCD and TMCD were determined in the CF#1 mice after i.p. administration. The induction of NTDs by M-TMCD and TMCD was evaluated after a single i.p. administration at day 8.5 of gestation in a highly inbred mouse strain (SWV) that is susceptible to valproic acidinduced neural tube defects.Results: In mice, M-TMCD afforded protection against maximal electroshock (MES)-induced, pentylenetetrazol (Metrazol)-induced, and bicuculline-induced seizures, as well as against 6-Hz "psychomotor" seizures and sound-induced seizures with ED 50 values of 99, 39, 81, 51, and 10 mg/kg, respectively. In rats, M-TMCD effectively prevented MES-and Metrazol-induced seizures and secondarily generalized seizures in hippocampal kindled rats (ED 50 values of 82, 45, and 39 mg/kg, respectively). Unlike M-TMCD, TMCD was active only against Metrazol-induced seizures in mice and rats (ED 50 values of 57 and 52 mg/kg, respectively). Neither M-TMCD nor TMCD was found to induce NTDs in SWV mice.Conclusions: The results obtained in this study show that M-TMCD is a broad-spectrum anticonvulsant drug that does not induce NTDs and support additional studies to evaluate its full therapeutic potential.

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Anticonvulsant Profile and Teratogenicity of N‐methyl‐tetramethylcyclopropyl Carboxamide: A New Antiepileptic Drug

et al. 2002

View full text Add to dashboard Cite

show abstract

“…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).…”

Section: Discussionmentioning

confidence: 92%

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

Lampen

Grimaldi²,

Nau³

2005

Mol Pharmacol

Self Cite

View full text Add to dashboard Cite

It has been suggested that the teratogenic effects of the antiepileptic drug valproic acid (VPA) is reflected in vitro by the differentiation of F9 cells, activation of peroxisome proliferatoractivated receptor ␦ (PPAR␦), and inhibition of histone deacetylases (HDACs). The aim of this study was to identify genes involved in the differentiation of F9 cells induced by VPA, teratogenic VPA derivatives, or the HDAC inhibitor trichostatin A (TSA) and to characterize the role of PPAR␦. Treatment of the cells with teratogenic VPA derivatives or TSA induced differentiation of F9 cells, mRNA, and protein expression of the neural cell adhesion molecule (NCAM) as well as activated the 5Ј-flanking region of the NCAM promoter, whereas nonteratogenic VPA derivatives had no effect at all. The polysialyltransferases [ST8SiaIV (PST1) and ST8SiaII] are responsible for the addition of polysialic acid (PSA) to NCAM. The mRNA expression of PST1 was highly induced by only teratogenic VPA derivatives and TSA. As shown by fluorescence-activated cell sorting analysis the level of PSA was higher after treatment of F9 cells with teratogenic VPA derivatives. It is interesting that overexpression of the PPAR␦ but not PPAR␣ or PPAR␥ in F9 cells resulted in higher induction of NCAM mRNA and protein expression and of PST1 mRNA expression (and a higher PSA level) than in mock-transfected F9 cells. Furthermore, repression of PPAR␦ activity in F9 cells inhibited these effects. We conclude that NCAM and PST1 are molecular markers in F9 cell differentiation caused by treatment with teratogenic VPA compounds or TSA and suggest that in addition to HDAC inhibition PPAR␦ is involved in the signaling pathway.

show abstract

“…The VPA derivatives S-2-pentyl-4-pentynoic acid and R-2-pentyl-4-pentynoic acid were synthesised according to the methods described before. 6,35,36 Standard GC-MS purity analysis procedures demonstrate a chemical purity of the derivatives Z98%, and after suitable derivatisation an enantiomeric purity of Z95% enantiomeric access of the chiral compounds. All VPA derivatives used in the in vitro experiments were dissolved in dimethylsulphoxide (DMSO) to give stock solutions of 1 M.…”

Section: Methodsmentioning

confidence: 99%

Valproic acid induces extracellular signal-regulated kinase 1/2 activation and inhibits apoptosis in endothelial cells

et al. 2005

View full text Add to dashboard Cite

The histone deacetylase (HDAC) inhibitor valproic acid (VPA) was recently shown to inhibit angiogenesis, but displays no toxicity in endothelial cells. Here, we demonstrate that VPA increases extracellular signal-regulated kinase 1/2 (ERK 1/2) phosphorylation in human umbilical vein endothelial cells (HUVEC). The investigation of structurally modified VPA derivatives revealed that the induction of ERK 1/2 phosphorylation is not correlated to HDAC inhibition. PD98059, a pharmacological inhibitor of the mitogenactivated protein kinase kinase 1/2, prevented the VPAinduced ERK 1/2 phosphorylation. In endothelial cells, ERK 1/2 phosphorylation is known to promote cell survival and angiogenesis. Our results showed that VPA-induced ERK 1/2 phosphorylation in turn causes phosphorylation of the antiapoptotic protein Bcl-2 and inhibits serum starvationinduced HUVEC apoptosis and cytochrome c release from the mitochondria. Moreover, the combination of VPA with PD98059 synergistically inhibited angiogenesis in vitro and in vivo.

show abstract

Studies on the teratogen pharmacophore of valproic acid analogues: evidence of interactions at a hydrophobic centre

Cited by 58 publications

References 47 publications

Anticonvulsant Profile and Teratogenicity of N‐methyl‐tetramethylcyclopropyl Carboxamide: A New Antiepileptic Drug

Anticonvulsant Profile and Teratogenicity of N‐methyl‐tetramethylcyclopropyl Carboxamide: A New Antiepileptic Drug

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

Valproic acid induces extracellular signal-regulated kinase 1/2 activation and inhibits apoptosis in endothelial cells

Contact Info

Product

Resources

About