title: 2-Aminoethyl methylphosphonate, a potent and rapidly acting antagonist of GABA(A)-ρ1 receptors.
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.
authors.affiliation: Lions of Illinois Eye Research Institute, Department of Ophthalmology and Visual Sciences, University of Illinois at Chicago, College of Medicine, Chicago, Illinois 60612, USA.
authors.forename: An
authors.initials: A
authors.lastname: Xie
authors.forename: Jun
authors.initials: J
authors.lastname: Yan
authors.forename: Lan
authors.initials: L
authors.lastname: Yue
authors.forename: Feng
authors.initials: F
authors.lastname: Feng
authors.forename: Fozia
authors.initials: F
authors.lastname: Mir
authors.forename: Heba
authors.initials: H
authors.lastname: Abdel-Halim
authors.forename: Mary
authors.initials: M
authors.lastname: Chebib
authors.forename: Guy C
authors.initials: GC
authors.lastname: Le Breton
authors.forename: Robert F
authors.initials: RF
authors.lastname: Standaert
authors.forename: Haohua
authors.initials: H
authors.lastname: Qian
authors.forename: David R
authors.initials: DR
authors.lastname: Pepperberg
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D005260:Female; D058787:GABA-A Receptor Antagonists / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D009943:Organophosphorus Compounds / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D018079:Receptors, GABA / Q000378:metabolism*; D011963:Receptors, GABA-A / Q000378:metabolism*; D013997:Time Factors; D014982:Xenopus laevis
chemical_list: D058787:GABA-A Receptor Antagonists; D009943:Organophosphorus Compounds; D018079:Receptors, GABA; D011963:Receptors, GABA-A; C523978:rho1 GABA(C) receptor, human; C032627:methylphosphonic acid