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

Lithium trialkylborohydrides were found to mono-dealkylate dialkylphosphonates rapidly (rate of cleavage Me, Bn > 1°). The reaction was applied to the synthesis of a new GABA C antagonist, 2-aminoethyl methylphosphonate ( 4a). Lithium trialkylborohydrides were found to effect rapid monodealkylati...

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Veröffentlicht in:Bioorganic & Medicinal Chemistry Letters 2007-07, Vol.17 (13), p.3745-3748
Hauptverfasser: Chowdhury, Sarwat, Muni, Niraj J., Greenwood, Nicholas P., Pepperberg, David R., Standaert, Robert F.
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container_end_page 3748
container_issue 13
container_start_page 3745
container_title Bioorganic & Medicinal Chemistry Letters
container_volume 17
creator Chowdhury, Sarwat
Muni, Niraj J.
Greenwood, Nicholas P.
Pepperberg, David R.
Standaert, Robert F.
description Lithium trialkylborohydrides were found to mono-dealkylate dialkylphosphonates rapidly (rate of cleavage Me, Bn > 1°). The reaction was applied to the synthesis of a new GABA C antagonist, 2-aminoethyl methylphosphonate ( 4a). 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 2N(CH 2) 2OP(OH)R, 4], a little-explored class of analogs of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). Compound 4a (R = Me) proved to be a potent antagonist at human ρ1 GABA C receptors (expressed in Xenopus laevis oocytes), with an IC 50 of 11.1 μM, but is inactive at α 1β 2γ 2 GABA A receptors.
doi_str_mv 10.1016/j.bmcl.2007.04.026
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(ORNL), Oak Ridge, TN (United States)</creatorcontrib><title>Phosphonic acid analogs of GABA through reductive dealkylation of phosphonic diesters with lithium trialkylborohydrides</title><title>Bioorganic &amp; Medicinal Chemistry Letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>Lithium trialkylborohydrides were found to mono-dealkylate dialkylphosphonates rapidly (rate of cleavage Me, Bn &gt; 1°). The reaction was applied to the synthesis of a new GABA C antagonist, 2-aminoethyl methylphosphonate ( 4a). 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 2N(CH 2) 2OP(OH)R, 4], a little-explored class of analogs of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). 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source Elsevier ScienceDirect Journals Complete - AutoHoldings; MEDLINE
subjects Animals
BASIC BIOLOGICAL SCIENCES
Biological and medical sciences
Borohydrides - chemistry
CATALYTIC EFFECTS
Chemistry, Pharmaceutical - methods
DEALKYLATION
Dose-Response Relationship, Drug
Drug Design
Esters - chemistry
GABA antagonists
GABA C receptors
GABAC receptors
Gabaergic and benzodiazepinic system
gamma-Aminobutyric Acid - analogs & derivatives
gamma-Aminobutyric Acid - chemistry
Inhibitory Concentration 50
Lithium
LITHIUM COMPOUNDS
Lithium trialkylborohydrides
Magnetic Resonance Spectroscopy
Medical sciences
Models, Chemical
NERVE CELLS
Neuropharmacology
Neurotransmitter Agents
Neurotransmitters. Neurotransmission. Receptors
OOCYTES
Oocytes - metabolism
Organophosphonates - chemical synthesis
Organophosphonates - chemistry
Pharmacology. Drug treatments
Phosphonate esters
phosphonate estes
PHOSPHONIC ACID ESTERS
RECEPTORS
SYNTHESIS
Xenopus laevis
title Phosphonic acid analogs of GABA through reductive dealkylation of phosphonic diesters with lithium trialkylborohydrides
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