title: 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.
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 muM) 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.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska 68198-5800, USA. bmathiascosta@unmc.edu
authors.forename: Blaise Mathias
authors.initials: BM
authors.lastname: Costa
authors.forename: Bihua
authors.initials: B
authors.lastname: Feng
authors.forename: Timur S
authors.initials: TS
authors.lastname: Tsintsadze
authors.forename: Richard M
authors.initials: RM
authors.lastname: Morley
authors.forename: Mark W
authors.initials: MW
authors.lastname: Irvine
authors.forename: Vera
authors.initials: V
authors.lastname: Tsintsadze
authors.forename: Natasha A
authors.initials: NA
authors.lastname: Lozovaya
authors.forename: David E
authors.initials: DE
authors.lastname: Jane
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Monaghan
mesh_terms: D000818:Animals; D018076:DNA, Complementary / Q000096:biosynthesis / Q000235:genetics; D003998:Dicarboxylic Acids / Q000494:pharmacology*; D015195:Drug Design; D004594:Electrophysiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D007608:Kainic Acid / Q000378:metabolism; D009865:Oocytes; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000187:drug effects / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000187:drug effects*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013569:Synapses / Q000187:drug effects*; D014982:Xenopus laevis
chemical_list: D018076:DNA, Complementary; D003998:Dicarboxylic Acids; D018691:Excitatory Amino Acid Antagonists; C120997:NR2A NMDA receptor; D010879:Piperazines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D007608:Kainic Acid
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