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.
Chowdhury
Sarwat
S
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, IL 60607-7056, USA.
Muni
Niraj J
NJ
Greenwood
Nicholas P
NP
Pepperberg
David R
DR
Standaert
Robert F
RF
D000818:Animals; D001894:Borohydrides / Q000737:chemistry*; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004952:Esters / Q000737:chemistry; D020128:Inhibitory Concentration 50; D008094:Lithium; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D018377:Neurotransmitter Agents; D009865:Oocytes / Q000378:metabolism; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry; D014982:Xenopus laevis; D005680:gamma-Aminobutyric Acid / Q000031:analogs & derivatives* / Q000737:chemistry*
D001894:Borohydrides; D004952:Esters; D018377:Neurotransmitter Agents; D063065:Organophosphonates; D005680:gamma-Aminobutyric Acid; D008094:Lithium