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 (2-AEMP), A POTENT AND RAPIDLY ACTING ANTAGONIST OF GABA<sub>A</sub>-ρ1 RECEPTORS
AID  - 10.1124/mol.111.071225
DP  - 2011 Jan 01
TA  - Molecular Pharmacology
PG  - mol.111.071225
4099  - http://molpharm.aspetjournals.org/content/early/2011/08/02/mol.111.071225.short
4100  - http://molpharm.aspetjournals.org/content/early/2011/08/02/mol.111.071225.full
AB  - 2-Aminoethyl methylphosphonate (2-AEMP), an analog of γ-aminobutyric acid (GABA), was recently 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’s, the pre-incubation 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.