Different characteristics of AMPA receptor agonists acting at AMPA receptors expressed in Xenopus oocytes

Different characteristics of AMPA receptor agonists acting at AMPA receptors expressed in Xenopus... A series of ( RS )-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) analogues were evaluated for activity at homo-oligomeric glutamate 1 -flop (Glu 1 -flop) receptors expressed in Xenopus oocytes, using the two-electrode voltage clamp technique. ( RS )-2-Amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA) (EC 50 , 2.4 μM), a homologue of AMPA having a carboxyl group as the terminal acidic functionality, was five times more potent than AMPA (EC 50 , 12 μM) and 20 times more potent than kainate (EC 50 , 46 μM). ( RS )-2-Amino-3-(3-hydroxy-5-trifluoromethyl-4-isoxazolyl)propionic acid (Tri-F-AMPA), in which an electronegative trifluoromethyl group is substituted for the methyl group on the isoxazole ring in the AMPA structure, was three times more potent than AMPA, whereas ( RS )-3-hydroxy-4,5,6,7-tetrahydroisoxazolo(5,4- c )pyridine-5-carboxylic acid (5-HPCA), a bicyclic analogue of AMPA with highly restricted conformational flexibility was 10 times less potent than AMPA. The limiting slope of log-log plots of Glu 1 -flop receptor currents versus low agonist concentrations had a value of 1.7 for ACPA and kainate compared to 1.5 for Tri-F-AMPA and 1.3 for 5-HPCA and AMPA. The amplitude of responses evoked by near saturating concentrations of the agonists varied more than 7-fold. The sequence of efficacy was ACPA = kainate > Tri-F-AMPA > AMPA > 5-HPCA. Moreover, when saturating concentrations of Tri-F-AMPA and kainate were co-applied, the response was significantly greater than when each of the agonists was applied separately. The potency of the antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo( f )quinoxaline (NBQX) (estimated K B , ∼ 200 nM), to block currents mediated by Glu 1 -flop receptors was similar for all of the agonists tested in this study. These results indicate that relatively minor changes in the molecular structure of AMPA are associated with marked effects on potency and efficacy. In particular, it is suggested that the acidity of the terminal group plays a major role in determining the degree of receptor activation in the steady state. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png European Journal of Pharmacology Elsevier

Different characteristics of AMPA receptor agonists acting at AMPA receptors expressed in Xenopus oocytes

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Publisher
Elsevier
Copyright
Copyright © 1996 Elsevier Ltd
ISSN
0014-2999
DOI
10.1016/0014-2999(96)00292-0
Publisher site
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Abstract

A series of ( RS )-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) analogues were evaluated for activity at homo-oligomeric glutamate 1 -flop (Glu 1 -flop) receptors expressed in Xenopus oocytes, using the two-electrode voltage clamp technique. ( RS )-2-Amino-3-(3-carboxy-5-methyl-4-isoxazolyl)propionic acid (ACPA) (EC 50 , 2.4 μM), a homologue of AMPA having a carboxyl group as the terminal acidic functionality, was five times more potent than AMPA (EC 50 , 12 μM) and 20 times more potent than kainate (EC 50 , 46 μM). ( RS )-2-Amino-3-(3-hydroxy-5-trifluoromethyl-4-isoxazolyl)propionic acid (Tri-F-AMPA), in which an electronegative trifluoromethyl group is substituted for the methyl group on the isoxazole ring in the AMPA structure, was three times more potent than AMPA, whereas ( RS )-3-hydroxy-4,5,6,7-tetrahydroisoxazolo(5,4- c )pyridine-5-carboxylic acid (5-HPCA), a bicyclic analogue of AMPA with highly restricted conformational flexibility was 10 times less potent than AMPA. The limiting slope of log-log plots of Glu 1 -flop receptor currents versus low agonist concentrations had a value of 1.7 for ACPA and kainate compared to 1.5 for Tri-F-AMPA and 1.3 for 5-HPCA and AMPA. The amplitude of responses evoked by near saturating concentrations of the agonists varied more than 7-fold. The sequence of efficacy was ACPA = kainate > Tri-F-AMPA > AMPA > 5-HPCA. Moreover, when saturating concentrations of Tri-F-AMPA and kainate were co-applied, the response was significantly greater than when each of the agonists was applied separately. The potency of the antagonist 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo( f )quinoxaline (NBQX) (estimated K B , ∼ 200 nM), to block currents mediated by Glu 1 -flop receptors was similar for all of the agonists tested in this study. These results indicate that relatively minor changes in the molecular structure of AMPA are associated with marked effects on potency and efficacy. In particular, it is suggested that the acidity of the terminal group plays a major role in determining the degree of receptor activation in the steady state.

Journal

European Journal of PharmacologyElsevier

Published: Jul 18, 1996

References

  • On the multiple-conductance single channels activated by excitatory amino acids in large cerebellar neurones of the rat
    Cull-Candy, S.G.; Usowicz, M.M.
  • Molecular neurobiology of glutamate receptors
    Gasic, G.P.; Hollmann, M.
  • Structural, conformational, and stereochemical requirements of central excitatory amino acid receptors
    Hansen, J.J.; Krogsgaard-Larsen, P.
  • Glutamate receptor channels in isolated patches from CA1 and CA3 pyramidal cells of rat hippocampal slices
    Jonas, P.; Sakmann, B.
  • heterocyclic excitatory amino acids
    Madsen, U.; Wong, E.H.F.
  • Effects of defolliculation on membrane current responses of Xenopus oocytes
    Miledi, R.; Woodward, R.M.
  • A comparison of the actions of agonists and antagonists at non-NMDA receptors of C fibres and motoneurons of the immature rat spinal cord in vitro
    Pook, P.; Brugger, F.; Hawkins, N.S.; Clark, K.C.; Watkins, J.C.; Evans, R.H.
  • Stereoselective effects of AMOA on non-NMDA receptors expressed in Xenopus oocytes
    Wahl, P.; Nielsen, B.; Krogsgaard-Larsen, P.; Hansen, J.J.; Schousboe, A.; Miledi, R.

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