@article {Xie965, author = {An Xie and Jun Yan and Lan Yue and Feng Feng and Fozia Mir and Heba Abdel-Halim and Mary Chebib and Guy C. Le Breton and Robert F. Standaert and Haohua Qian and David R. Pepperberg}, title = {2-Aminoethyl Methylphosphonate, a Potent and Rapidly Acting Antagonist of GABAA-ρ1 Receptors}, volume = {80}, number = {6}, pages = {965--978}, year = {2011}, doi = {10.1124/mol.111.071225}, publisher = {American Society for Pharmacology and Experimental Therapeutics}, abstract = {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{\textquoteright}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{\textquoteright}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{\textquoteright}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.}, issn = {0026-895X}, URL = {https://molpharm.aspetjournals.org/content/80/6/965}, eprint = {https://molpharm.aspetjournals.org/content/80/6/965.full.pdf}, journal = {Molecular Pharmacology} }