Phosphonic acid analogs of GABA through reductive dealkylation of phosphonic diesters with lithium trialkylborohydrides

  • Bioorg Med Chem Lett. 2007 Jul 1;17(13):3745-8. doi: 10.1016/j.bmcl.2007.04.026.
Sarwat Chowdhury  1 ,  Niraj J Muni ,  Nicholas P Greenwood ,  David R Pepperberg ,  Robert F Standaert
Affiliations
  • 1. Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607-7056, USA.
PMID: 17467985 DOI: 10.1016/j.bmcl.2007.04.026
Abstract

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.