Phosphonic acid analogs of GABA through reductive dealkylation of phosphonic diesters with lithium trialkylborohydrides.
Lithium trialkylborohydrides were found to effect rapid monodealkylation of phosphonic diesters, and this reaction was applied to the synthesis of alkylphosphonic acid 2-aminoethyl esters [H(2)N(CH(2))(2)OP(OH)R, 4], a little-explored class of analogs of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA). Compound 4a (R=Me) proved to be a potent antagonist at human rho1 GABA(C) receptors (expressed in Xenopus laevis oocytes), with an IC(50) of 11.1 microM, but is inactive at alpha(1)beta(2)gamma(2) GABA(A) receptors.
PubMed ID: 17467985
Article link: Bioorg Med Chem Lett.
Grant support: EY001792 NEI NIH HHS , EY013693 NEI NIH HHS , EY016094 NEI NIH HHS , R01 EY016094-01A1 NEI NIH HHS , R03 EY013693-03 NEI NIH HHS , R01 EY016094 NEI NIH HHS , R03 EY013693 NEI NIH HHS