Valnoctamide, valpromide and valnoctic acid are much less teratogenic in mice than valproic acid

The teratogenic properties of valproic acid (VPA) and its analogues depend to a great extent on their chemical structure. We investigated the structure-teratogenicity relationships of VPA, its structural isomer, valnoctic acid (VCA), and their two amide analogues, valpromide (VPD) and valnoctamide (VCD), respectively. Each substance was injected (3 mmol/kg) in NMRI-mice on the morning of day 8 of gestation. Embryolethality, fetal weight and exencephaly rates were recorded on day 18 of gestation. VPA caused 53% exencephaly, VPD induced 6%, VCA and VCD produced only 1% exencephaly (control values between 0 and 1%). VPA-treated mice also had increased embryolethality rates (52%). There was no significant change of embryolethality in the other treatment groups. Pharmacokinetic studies showed that VCD was eliminated from plasma at a slower rate than VPA. Also, the residual teratogenic activity of VPD was not accounted for by the relatively small amounts of its hydrolysis product VPA. This study indicates that VPD, VCA and VCD were distinctly less teratogenic than VPA. Apparently the amidation of the free carboxylic group and/or methyl-substitution at the beta-position of the carbon chain greatly decreased the teratogenic activity of VPA.