2-Aminoethyl Methylphosphonate, a Potent and Rapidly Acting Antagonist of GABAA-ρ1 Receptors
Abstract
All three classes of receptors for the inhibitory neurotransmitter GABA (GABAR) are expressed in the retina. This study investigated roles of GABAR, especially GABA(C)R (GABA(A)-rho), in retinal signaling in vivo by studying effects on the mouse electroretinogram (ERG) of genetic deletion of GABA(C)R versus pharmacological blockade using receptor antagonists. Brief full-field flash ERGs were recorded from anesthetized GABA(C)R(-/-) mice, and WT C57BL/6 (B6) mice, before and after intravitreal injection of GABA(C)R antagonists, TPMPA, 3-APMPA, or the more recently developed 2-AEMP; GABA(A)R antagonist, SR95531; GABA(B)R antagonist, CGP, and agonist, baclofen. Intravitreal injections of TPMPA and SR95531 were also made in Brown Norway rats. The effect of 2-AEMP on GABA-induced current was tested directly in isolated rat rod bipolar cells, and 2-AEMP was found to preferentially block GABA(C)R in those cells. Maximum amplitudes of dark (DA) and light-adapted (LA) ERG b-waves were reduced in GABA(C)R(-/-) mice, compared to B6 mice, by 30-60%; a-waves were unaltered and oscillatory potential amplitudes were increased. In B6 mice, after injection of TPMPA (also in rats), 3-APMPA or 2-AEMP, ERGs became similar to ERGs of GABA(C)R(-/-) mice. Blockade of GABA(A)Rs and GABA(B)Rs, or agonism of GABA(B)Rs did not alter B6 DA b-wave amplitude. The negative scotopic thresholdmore »
- Authors:
-
- Univ. of Illinois, Chicago, IL (United States)
- Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
- Univ. of Sydney, NSW (Australia)
- Publication Date:
- Research Org.:
- Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)
- Sponsoring Org.:
- Work for Others (WFO)
- OSTI Identifier:
- 1334416
- Grant/Contract Number:
- AC05-00OR22725
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Molecular Pharmacology
- Additional Journal Information:
- Journal Volume: 80; Journal Issue: 6; Journal ID: ISSN 0026-895X
- Publisher:
- American Society for Pharmacology and Experimental Therapeutics
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES; neurotransmitter; GABA; structure-activity relationships; pharmacology; ion channel
Citation Formats
Xie, A., Yan, J., Yue, L., Feng, F., Mir, F., Abdel-Halim, H., Chebib, M., Le Breton, G. C., Standaert, R. F., Qian, H., and Pepperberg, D. R. 2-Aminoethyl Methylphosphonate, a Potent and Rapidly Acting Antagonist of GABAA-ρ1 Receptors. United States: N. p., 2011.
Web. doi:10.1124/mol.111.071225.
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. 2-Aminoethyl Methylphosphonate, a Potent and Rapidly Acting Antagonist of GABAA-ρ1 Receptors. United States. https://doi.org/10.1124/mol.111.071225
Xie, A., Yan, J., Yue, L., Feng, F., Mir, F., Abdel-Halim, H., Chebib, M., Le Breton, G. C., Standaert, R. F., Qian, H., and Pepperberg, D. R. Tue .
"2-Aminoethyl Methylphosphonate, a Potent and Rapidly Acting Antagonist of GABAA-ρ1 Receptors". United States. https://doi.org/10.1124/mol.111.071225. https://www.osti.gov/servlets/purl/1334416.
@article{osti_1334416,
title = {2-Aminoethyl Methylphosphonate, a Potent and Rapidly Acting Antagonist of GABAA-ρ1 Receptors},
author = {Xie, A. and Yan, J. and Yue, L. and Feng, F. and Mir, F. and Abdel-Halim, H. and Chebib, M. and Le Breton, G. C. and Standaert, R. F. and Qian, H. and Pepperberg, D. R.},
abstractNote = {All three classes of receptors for the inhibitory neurotransmitter GABA (GABAR) are expressed in the retina. This study investigated roles of GABAR, especially GABA(C)R (GABA(A)-rho), in retinal signaling in vivo by studying effects on the mouse electroretinogram (ERG) of genetic deletion of GABA(C)R versus pharmacological blockade using receptor antagonists. Brief full-field flash ERGs were recorded from anesthetized GABA(C)R(-/-) mice, and WT C57BL/6 (B6) mice, before and after intravitreal injection of GABA(C)R antagonists, TPMPA, 3-APMPA, or the more recently developed 2-AEMP; GABA(A)R antagonist, SR95531; GABA(B)R antagonist, CGP, and agonist, baclofen. Intravitreal injections of TPMPA and SR95531 were also made in Brown Norway rats. The effect of 2-AEMP on GABA-induced current was tested directly in isolated rat rod bipolar cells, and 2-AEMP was found to preferentially block GABA(C)R in those cells. Maximum amplitudes of dark (DA) and light-adapted (LA) ERG b-waves were reduced in GABA(C)R(-/-) mice, compared to B6 mice, by 30-60%; a-waves were unaltered and oscillatory potential amplitudes were increased. In B6 mice, after injection of TPMPA (also in rats), 3-APMPA or 2-AEMP, ERGs became similar to ERGs of GABA(C)R(-/-) mice. Blockade of GABA(A)Rs and GABA(B)Rs, or agonism of GABA(B)Rs did not alter B6 DA b-wave amplitude. The negative scotopic threshold response (nSTR) was slightly less sensitive in GABA(C)R(-/-) than in B6 mice, and unaltered by 2-AEMP. However, amplitudes of nSTR and photopic negative response (PhNR), both of which originate from inner retina, were enhanced by TPMPA and 3-APMPA, each of which has GABA(B) agonist properties, and further increased by baclofen. The finding that genetic deletion of GABA(C)R, the GABA(C)R antagonist 2-AEMP, and other antagonists all reduced ERG b-wave amplitude, supports a role for CABA(C)R in determining the maximum response amplitude of bipolar cells contributing to the b-wave. GABA(C)R antagonists differed in their effects on nSTR and PhNR; antagonists with GABA(B) agonist properties enhanced light-driven responses whereas 2-AEMP did not.},
doi = {10.1124/mol.111.071225},
journal = {Molecular Pharmacology},
number = 6,
volume = 80,
place = {United States},
year = {Tue Aug 02 00:00:00 EDT 2011},
month = {Tue Aug 02 00:00:00 EDT 2011}
}
Web of Science
Works referenced in this record:
A Molecular Basis for Agonist and Antagonist Actions at GABA C Receptors
journal, April 2008
- Abdel-Halim, Heba; Hanrahan, Jane R.; Hibbs, David E.
- Chemical Biology & Drug Design, Vol. 71, Issue 4
Insights into the activation mechanism of ρ1GABA receptors obtained by coexpression of wild type and activation-impaired subunits
journal, March 1996
- Amin, Jahanshah; Weiss, David S.
- Proceedings of the Royal Society of London. Series B: Biological Sciences, Vol. 263, Issue 1368, p. 273-282
Phosphorus analogs of .gamma.-aminobutyric acid, a new class of anticonvulsants
journal, May 1984
- Cates, Lindley A.; Li, Ven Shun; Yakshe, Chriss C.
- Journal of Medicinal Chemistry, Vol. 27, Issue 5
Channel opening locks agonist onto the GABAC receptor
journal, March 1999
- Chang, Yongchang; Weiss, David S.
- Nature Neuroscience, Vol. 2, Issue 3
Gabac Receptor ion Channels
journal, November 2004
- Chebib, M.
- Clinical and Experimental Pharmacology and Physiology, Vol. 31, Issue 11
(3-Aminocyclopentyl)methylphosphinic acids: Novel GABAC receptor antagonists
journal, March 2007
- Chebib, Mary; Hanrahan, Jane R.; Kumar, Rohan J.
- Neuropharmacology, Vol. 52, Issue 3
Analogues of γ -aminobutyric acid (GABA) and trans -4-aminocrotonic acid (TACA) substituted in the 2 position as GABA C receptor antagonists: C2-substituted analogues of GABA and TACA
journal, December 1997
- Chebib, Mary; Vandenberg, Robert J.; Johnston, Graham A. R.
- British Journal of Pharmacology, Vol. 122, Issue 8
The time course of glutamate in the synaptic cleft
journal, November 1992
- Clements, J.; Lester, R.; Tong, G.
- Science, Vol. 258, Issue 5087
Phosphonic acid analogs of GABA through reductive dealkylation of phosphonic diesters with lithium trialkylborohydrides
journal, July 2007
- Chowdhury, Sarwat; Muni, Niraj J.; Greenwood, Nicholas P.
- Bioorganic & Medicinal Chemistry Letters, Vol. 17, Issue 13
Expression of GABA Receptor ρ1 and ρ2 Subunits in the Retina and Brain of the Rat
journal, July 1995
- Enz, Ralf; Brandstätter, Johann Helmut; Hartveit, Espen
- European Journal of Neuroscience, Vol. 7, Issue 7
Glide: A New Approach for Rapid, Accurate Docking and Scoring. 1. Method and Assessment of Docking Accuracy
journal, March 2004
- Friesner, Richard A.; Banks, Jay L.; Murphy, Robert B.
- Journal of Medicinal Chemistry, Vol. 47, Issue 7
Extra Precision Glide: Docking and Scoring Incorporating a Model of Hydrophobic Enclosure for Protein−Ligand Complexes
journal, October 2006
- Friesner, Richard A.; Murphy, Robert B.; Repasky, Matthew P.
- Journal of Medicinal Chemistry, Vol. 49, Issue 21
Phosphinic Acid Analogs of GABA. 1. New Potent and Selective GABAB Agonists
journal, August 1995
- Froestl, Wolfgang; Mickel, Stuart J.; Hall, Roger G.
- Journal of Medicinal Chemistry, Vol. 38, Issue 17
Phosphinic Acid Analogs of GABA. 2. Selective, Orally Active GABAB Antagonists
journal, August 1995
- Froestl, Wolfgang; Mickel, Stuart J.; von Sprecher, Georg
- Journal of Medicinal Chemistry, Vol. 38, Issue 17
Binding of Muscimol-Conjugated Quantum Dots to GABA C Receptors
journal, December 2006
- Gussin, Hélène A.; Tomlinson, Ian D.; Little, Deborah M.
- Journal of the American Chemical Society, Vol. 128, Issue 49
Glide: A New Approach for Rapid, Accurate Docking and Scoring. 2. Enrichment Factors in Database Screening
journal, March 2004
- Halgren, Thomas A.; Murphy, Robert B.; Friesner, Richard A.
- Journal of Medicinal Chemistry, Vol. 47, Issue 7
Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations
journal, September 2005
- Hansen, Scott B.; Sulzenbacher, Gerlind; Huxford, Tom
- The EMBO Journal, Vol. 24, Issue 20
Molecular modeling of the GABAC receptor ligand-binding domain
journal, October 2005
- Harrison, Neil J.; Lummis, Sarah C. R.
- Journal of Molecular Modeling, Vol. 12, Issue 3
Enantioselective actions of 4-amino-3-hydroxybutanoic acid and (3-amino-2-hydroxypropyl)methylphosphinic acid at recombinant GABAC receptors
journal, January 2008
- Hinton, Tina; Chebib, Mary; Johnston, Graham A. R.
- Bioorganic & Medicinal Chemistry Letters, Vol. 18, Issue 1
Biological activity of 3-aminopropyl (methyl) phosphinic acid, a potent and selective GABAB agonist with CNS activity
journal, April 1993
- Howson, William; Mistry, Jaystree; Broekman, marianne
- Bioorganic & Medicinal Chemistry Letters, Vol. 3, Issue 4
Microscopic Kinetics and Energetics Distinguish GABAA Receptor Agonists from Antagonists
journal, November 2001
- Jones, Mathew V.; Jonas, Peter; Sahara, Yoshinori
- Biophysical Journal, Vol. 81, Issue 5
Desensitized states prolong GABAA channel responses to brief agonist pulses
journal, July 1995
- Jones, Mathew V.; Westbrook, Gary L.
- Neuron, Vol. 15, Issue 1
Development and Testing of the OPLS All-Atom Force Field on Conformational Energetics and Properties of Organic Liquids
journal, January 1996
- Jorgensen, William L.; Maxwell, David S.; Tirado-Rives, Julian
- Journal of the American Chemical Society, Vol. 118, Issue 45
Characterization of isoprostane signaling: Evidence for a unique coordination profile of 8-iso-PGF2α with the thromboxane A2 receptor, and activation of a separate cAMP-dependent inhibitory pathway in human platelets
journal, June 2008
- Khasawneh, Fadi T.; Huang, Jin-Sheng; Mir, Fozia
- Biochemical Pharmacology, Vol. 75, Issue 12
Differential Mapping of the Amino Acids Mediating Agonist and Antagonist Coordination with the Human Thromboxane A 2 Receptor Protein
journal, July 2006
- Khasawneh, Fadi T.; Huang, Jin-Sheng; Turek, Joseph W.
- Journal of Biological Chemistry, Vol. 281, Issue 37
A Convenient Route for Monodealkylation of Diethyl Phosphonates
journal, September 1997
- Krawczyk, Henryk
- Synthetic Communications, Vol. 27, Issue 18
Phosphinic, phosphonic and seleninic acid bioisosteres of isonipecotic acid as novel and selective GABAC receptor antagonists
journal, June 2003
- Krehan, Dorte; Frølund, Bente; Krogsgaard-Larsen, Povl
- Neurochemistry International, Vol. 42, Issue 7
Synaptic mechanisms that shape visual signaling at the inner retina
book, January 2005
- Lukasiewicz, Peter D.
- Progress in Brain Research
A Cation-π Binding Interaction with a Tyrosine in the Binding Site of the GABAC Receptor
journal, September 2005
- Lummis, Sarah C. R.; L. Beene, Darren; Harrison, Neil J.
- Chemistry & Biology, Vol. 12, Issue 9
The first selective antagonist for a GABAC receptor
journal, September 1996
- Murata, Yoshinori; Woodward, Richard M.; Miledi, Ricardo
- Bioorganic & Medicinal Chemistry Letters, Vol. 6, Issue 17
Neurotransmitter analog tethered to a silicon platform for neuro-bioMEMS applications
journal, January 2004
- Nehilla, Barrett J.; Popat, Ketul C.; Vu, Tania Q.
- Biotechnology and Bioengineering, Vol. 87, Issue 5
Nanosculpting reversed wavelength sensitivity into a photoswitchable iGluR
journal, April 2009
- Numano, R.; Szobota, S.; Lau, A. Y.
- Proceedings of the National Academy of Sciences, Vol. 106, Issue 16
GABAA receptors: Subtypes provide diversity of function and pharmacology
journal, January 2009
- Olsen, Richard W.; Sieghart, Werner
- Neuropharmacology, Vol. 56, Issue 1
Influence of GABAAR Monoliganded States on GABAergic Responses
journal, February 2011
- Petrini, E. M.; Nieus, T.; Ravasenga, T.
- Journal of Neuroscience, Vol. 31, Issue 5
Novel GABA responses from rod- driven retinal horizontal cells
journal, January 1993
- Qian, Haohua; Dowling, John E.
- Nature, Vol. 361, Issue 6408
Assembly and characterization of biofunctional neurotransmitter-immobilized surfaces for interaction with postsynaptic membrane receptors
journal, June 2003
- Saifuddin, Uroosa; Vu, Tania Q.; Rezac, Miroslav
- Journal of Biomedical Materials Research, Vol. 66A, Issue 1
Mapping the ρ 1 GABA C Receptor Agonist Binding Pocket: CONSTRUCTING A COMPLETE MODEL
journal, November 2004
- Sedelnikova, Anna; Smith, Craig D.; Zakharkin, Stanislav O.
- Journal of Biological Chemistry, Vol. 280, Issue 2
The GABA ρ1 subunit interacts with a cellular retinoic acid binding protein in mammalian retina
journal, January 2005
- Song, X. -Q.; Meng, F.; Ramsey, D. J.
- Neuroscience, Vol. 136, Issue 2
Identification of a Tyrosine in the Agonist Binding Site of the Homomeric ρ1 γ-Aminobutyric Acid (GABA) Receptor That, When Mutated, Produces Spontaneous Opening
journal, September 2002
- Torres, Viviana I.; Weiss, David S.
- Journal of Biological Chemistry, Vol. 277, Issue 46
Intraburst kinetic properties of the GABAA receptor main conductance state of mouse spinal cord neurones in culture.
journal, April 1990
- Twyman, R. E.; Rogers, C. J.; Macdonald, R. L.
- The Journal of Physiology, Vol. 423, Issue 1
Allosteric control of an ionotropic glutamate receptor with an optical switch
journal, December 2005
- Volgraf, Matthew; Gorostiza, Pau; Numano, Rika
- Nature Chemical Biology, Vol. 2, Issue 1
Activation of membrane receptors by a neurotransmitter conjugate designed for surface attachment
journal, May 2005
- Vu, Tania Q.; Chowdhury, Sarwat; Muni, Niraj J.
- Biomaterials, Vol. 26, Issue 14
Establishing an Ion Pair Interaction in the Homomeric ρ1 γ-Aminobutyric Acid Type A Receptor That Contributes to the Gating Pathway
journal, July 2007
- Wang, Jinti; Lester, Henry A.; Dougherty, Dennis A.
- Journal of Biological Chemistry, Vol. 282, Issue 36
Works referencing / citing this record:
Striatal Neurodegeneration that Mimics Huntington’s Disease Modifies GABA-induced Currents
journal, December 2018
- Flores-Hernández, Jorge; Garzón-Vázquez, Jeanette; Hernández-Carballo, Gustavo
- Brain Sciences, Vol. 8, Issue 12