2-Aminoethyl methylphosphonate, a potent and rapidly acting antagonist of GABA A-ρ1 receptors

An Xie, Jun Yan, Lan Yue, Feng Feng, Fozia Mir, Heba Abdel-Halim, Mary Chebib, Guy C. Le Breton, Robert F. Standaert, Haohua Qian, David R. Pepperberg

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

2-Aminoethyl methylphosphonate (2-AEMP), an analog of GABA, has been found to exhibit antagonist activity at GABA A-ρ1 (also known as ρ1 GABA C) receptors. The present study was undertaken to elucidate 2-AEMP's action and to test the activities of 2-AEMP analogs. Whole-cell patch-clamp techniques were used to record membrane currents in neuroblastoma cells stably transfected with human GABA A-ρ1 receptors. The action of 2-AEMP was compared with that of 1,2,5,6-tetrahydropyridin-4-yl methylphosphinic acid (TPMPA), a commonly used GABA A-ρ1 antagonist. With 10 μM GABA, 2-AEMP's IC 50 (18 μM) differed by less than 2.5-fold from that of TPMPA (7 μM), and results obtained were consistent with a primarily competitive mode of inhibition by 2-AEMP. Terminating the presentation of 2-AEMP or TPMPA in the presence of GABA produced a release from inhibition. However, the rate of inhibition release upon the termination of 2-AEMP considerably exceeded that determined with termination of TPMPA. Moreover, when presented at concentrations near their respective IC 50 values, the preincubation period associated with 2-AEMP's onset of inhibition was much shorter than that for TPMPA. Analogs of 2-AEMP possessing a benzyl or n-butyl rather than a methyl substituent at the phosphorus atom, as well as analogs bearing a C-methyl substituent on the aminoethyl side chain, exhibited reduced potency relative to 2-AEMP. Of these analogs, only (R)-2-aminopropyl methylphosphonate significantly diminished the response to 10 μM GABA. Structure-activity relationships are discussed in the context of molecular modeling of ligand binding to the antagonist binding site of the GABA A-ρ1 receptor.

Original languageEnglish (US)
Pages (from-to)965-978
Number of pages14
JournalMolecular Pharmacology
Volume80
Issue number6
DOIs
StatePublished - Dec 1 2011
Externally publishedYes

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    Xie, A., Yan, J., Yue, L., Feng, F., Mir, F., Abdel-Halim, H., Chebib, M., Le Breton, G. C., Standaert, R. F., Qian, H., & Pepperberg, D. R. (2011). 2-Aminoethyl methylphosphonate, a potent and rapidly acting antagonist of GABA A-ρ1 receptors. Molecular Pharmacology, 80(6), 965-978. https://doi.org/10.1124/mol.111.071225