N-methyl-D-aspartate (NMDA) receptor NR2 subunit selectivity of a series of novel piperazine-2,3-dicarboxylate derivatives

Preferential blockade of extrasynaptic NMDA receptors in the rat hippocampal CA3-CA1 synapse

Blaise Mathias Costa, Bihua Feng, Timur S. Tsintsadze, Richard M. Morley, Mark W. Irvine, Vera Tsintsadze, Natasha A. Lozovaya, David E. Jane, Daniel T Monaghan

Research output: Contribution to journalArticle

37 Citations (Scopus)

Abstract

N-Methyl-D-aspartate (NMDA) receptor antagonists that are highly selective for specific NMDA receptor 2 (NR2) subunits have several potential therapeutic applications; however, to date, only NR2B-selective antagonists have been described. Whereas most glutamate binding site antagonists display a common pattern of NR2 selectivity, NR2A > NR2B > NR2C > NR2D (high to low affinity), (2S*,3R*)-1-(phenanthrene-2-carbonyl) piperazine-2,3-dicarboxylic acid (PPDA) has a low selectivity for NR2C- and NR2D-containing NMDA receptors. A series of PPDA derivatives were synthesized and then tested at recombinant NMDA receptors expressed in Xenopus laevis oocytes. In addition, the optical isomers of PPDA were resolved; the (-) isomer displayed a 50- to 80-fold greater potency than the (+) isomer. Replacement of the phenanthrene moiety of PPDA with naphthalene or anthracene did not improve selectivity. However, phenylazobenzoyl (UBP125) or phenylethynylbenzoyl (UBP128) substitution significantly improved selectivity for NR2B-, NR2C-, and NR2D-containing receptors over NR2A-containing NMDA receptors. Phenanthrene attachment at the 3 position [(2R*,3S*)-1-(phenanthrene-3-carbonyl) piperazine-2,3-dicarboxylic acid (UBP141); (2R*,3S*)-1-(9- bromophenanthrene-3-carbonyl)piperazine-2,3-dicarboxylic acid (UBP145); (2R*,3S*)-1-(9-chlorophenanthrene-3-carbonyl)piperazine-2, 3-dicarboxylic acid (UBP160); and (2R*,3S*)-1-(9-iodophenanthrene-3- carbonyl)piperazine-2,3-dicarboxylic acid (UBP161)] displayed improved NR2D selectivity. UBP141 and its 9-brominated homolog (UBP145) both display a 7- to 10- fold selectivity for NR2D-containing receptors over NR2B- or NR2A-containing receptors. Schild analysis indicates that these two compounds are competitive glutamate binding site antagonists. Consistent with a physiological role for NR2D-containing receptors in the hippocampus, UBP141 (5 μM) displayed greater selectivity than PPDA for inhibiting the slow-decaying component of the NMDA receptor-mediated CA3-CA1 synaptic response in rat hippocampal slices. UBP125, UBP128, UBP141, and UBP145 may be useful tools for determining the function of NMDA receptor subtypes.

Original languageEnglish (US)
Pages (from-to)618-626
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume331
Issue number2
DOIs
StatePublished - Nov 1 2009

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Dicarboxylic Acids
N-Methyl-D-Aspartate Receptors
Synapses
Glutamic Acid
Binding Sites
Competitive Binding
piperazine
Xenopus laevis
Oocytes
Hippocampus
phenanthrene

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

N-methyl-D-aspartate (NMDA) receptor NR2 subunit selectivity of a series of novel piperazine-2,3-dicarboxylate derivatives : Preferential blockade of extrasynaptic NMDA receptors in the rat hippocampal CA3-CA1 synapse. / Costa, Blaise Mathias; Feng, Bihua; Tsintsadze, Timur S.; Morley, Richard M.; Irvine, Mark W.; Tsintsadze, Vera; Lozovaya, Natasha A.; Jane, David E.; Monaghan, Daniel T.

In: Journal of Pharmacology and Experimental Therapeutics, Vol. 331, No. 2, 01.11.2009, p. 618-626.

Research output: Contribution to journalArticle

Costa, Blaise Mathias ; Feng, Bihua ; Tsintsadze, Timur S. ; Morley, Richard M. ; Irvine, Mark W. ; Tsintsadze, Vera ; Lozovaya, Natasha A. ; Jane, David E. ; Monaghan, Daniel T. / N-methyl-D-aspartate (NMDA) receptor NR2 subunit selectivity of a series of novel piperazine-2,3-dicarboxylate derivatives : Preferential blockade of extrasynaptic NMDA receptors in the rat hippocampal CA3-CA1 synapse. In: Journal of Pharmacology and Experimental Therapeutics. 2009 ; Vol. 331, No. 2. pp. 618-626.
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abstract = "N-Methyl-D-aspartate (NMDA) receptor antagonists that are highly selective for specific NMDA receptor 2 (NR2) subunits have several potential therapeutic applications; however, to date, only NR2B-selective antagonists have been described. Whereas most glutamate binding site antagonists display a common pattern of NR2 selectivity, NR2A > NR2B > NR2C > NR2D (high to low affinity), (2S*,3R*)-1-(phenanthrene-2-carbonyl) piperazine-2,3-dicarboxylic acid (PPDA) has a low selectivity for NR2C- and NR2D-containing NMDA receptors. A series of PPDA derivatives were synthesized and then tested at recombinant NMDA receptors expressed in Xenopus laevis oocytes. In addition, the optical isomers of PPDA were resolved; the (-) isomer displayed a 50- to 80-fold greater potency than the (+) isomer. Replacement of the phenanthrene moiety of PPDA with naphthalene or anthracene did not improve selectivity. However, phenylazobenzoyl (UBP125) or phenylethynylbenzoyl (UBP128) substitution significantly improved selectivity for NR2B-, NR2C-, and NR2D-containing receptors over NR2A-containing NMDA receptors. Phenanthrene attachment at the 3 position [(2R*,3S*)-1-(phenanthrene-3-carbonyl) piperazine-2,3-dicarboxylic acid (UBP141); (2R*,3S*)-1-(9- bromophenanthrene-3-carbonyl)piperazine-2,3-dicarboxylic acid (UBP145); (2R*,3S*)-1-(9-chlorophenanthrene-3-carbonyl)piperazine-2, 3-dicarboxylic acid (UBP160); and (2R*,3S*)-1-(9-iodophenanthrene-3- carbonyl)piperazine-2,3-dicarboxylic acid (UBP161)] displayed improved NR2D selectivity. UBP141 and its 9-brominated homolog (UBP145) both display a 7- to 10- fold selectivity for NR2D-containing receptors over NR2B- or NR2A-containing receptors. Schild analysis indicates that these two compounds are competitive glutamate binding site antagonists. Consistent with a physiological role for NR2D-containing receptors in the hippocampus, UBP141 (5 μM) displayed greater selectivity than PPDA for inhibiting the slow-decaying component of the NMDA receptor-mediated CA3-CA1 synaptic response in rat hippocampal slices. UBP125, UBP128, UBP141, and UBP145 may be useful tools for determining the function of NMDA receptor subtypes.",
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T1 - N-methyl-D-aspartate (NMDA) receptor NR2 subunit selectivity of a series of novel piperazine-2,3-dicarboxylate derivatives

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AU - Costa, Blaise Mathias

AU - Feng, Bihua

AU - Tsintsadze, Timur S.

AU - Morley, Richard M.

AU - Irvine, Mark W.

AU - Tsintsadze, Vera

AU - Lozovaya, Natasha A.

AU - Jane, David E.

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