PT  - JOURNAL ARTICLE
AU  - An Xie
AU  - Jun Yan
AU  - Lan Yue
AU  - Feng Feng
AU  - Fozia Mir
AU  - Heba Abdel-Halim
AU  - Mary Chebib
AU  - Guy C. Le Breton
AU  - Robert F. Standaert
AU  - Haohua Qian
AU  - David R. Pepperberg
TI  - 2-Aminoethyl Methylphosphonate, a Potent and Rapidly Acting Antagonist of GABA<sub>A</sub>-ρ1 Receptors
AID  - 10.1124/mol.111.071225
DP  - 2011 Dec 01
TA  - Molecular Pharmacology
PG  - 965--978
VI  - 80
IP  - 6
4099  - http://molpharm.aspetjournals.org/content/80/6/965.short
4100  - http://molpharm.aspetjournals.org/content/80/6/965.full
SO  - Mol Pharmacol2011 Dec 01; 80
AB  - 2-Aminoethyl methylphosphonate (2-AEMP), an analog of GABA, has been found to exhibit antagonist activity at GABAA-ρ1 (also known as ρ1 GABAC) 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 GABAA-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 GABAA-ρ1 antagonist. With 10 μM GABA, 2-AEMP's IC50 (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 IC50 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 GABAA-ρ1 receptor.