Phosphorus GABA Analogues as Potential Prodrugs.

Analogues of γ-aminobutyric acid (GABA), wherein a P=O moiety is separated by three carbon atoms from an amino group, were incorporated into Schiff bases as potential acid-labile carrier molecules. These include 3-aminophenylphosphonic acid, its dimethyl ester and its previously unreported N,N'-diisopropylphosphonodiamide. A benzophenone derivative of GABA was also synthesized.A study of the degrees of in vitro hydrolysis of four Schiff bases indicated that lability of the C=N bond is determined by electronic influences of ring substituents.All new products were tested for abilities to inhibit maximal electroshock- and subcutaneous pentylenetetrazol (Metrazol)-induced seizures in mice.Activity was found only in the former system with moderate inhibition displayed by two dimethyl ester and the GABA Schiff bases.