Structure-activity Analysis of a Novel NR2C/NR2D-preferring NMDA Receptor Antagonist: 1-(phenanthrene-2-carbonyl) Piperazine-2,3-dicarboxylic Acid

Overview

Journal Br J Pharmacol

Publisher Wiley

Specialty Pharmacology

Date 2004 Jan 14

PMID 14718249

Citations 80

Authors

Bihua Feng

Heong W Tse

Donald A Skifter

Richard Morley

David E Jane

Daniel T Monaghan

Affiliations

Soon will be listed here.

Abstract

(2S*,3R*)-1-(biphenyl-4-carbonyl)piperazine-2,3-dicarboxylic acid (PBPD) is a moderate affinity, competitive N-methyl-d-aspartate (NMDA) receptor antagonist with an atypical pattern of selectivity among NMDA receptor 2 subunit (NR2) subunits. We now describe the activity of several derivatives of PBPD tested at both rat brain NMDA receptors using l-[3H]-glutamate binding assays and at recombinant receptors expressed in Xenopus oocytes. Substituting various branched ring structures for the biphenyl group of PBPD reduced NMDA receptor activity. However, substituting linearly arranged ring structures - fluorenone or phenanthrene groups - retained or enhanced activity. Relative to PBPD, the phenanthrene derivative (2S*, 3R*)-1-(phenanthrene-2-carbonyl)piperazine-2,3-dicarboxylic acid (PPDA) displayed a 30- to 78-fold increase in affinity for native NMDA receptors. At recombinant receptors, PPDA displayed a 16-fold (NR2B) to 94-fold (NR2C) increase in affinity over PBPD. Replacement of the biphenyl group of PBPD with a 9-oxofluorene ring system resulted in small changes in receptor affinity and subtype selectivity. 2'-Bromo substitution on the biphenyl group of PBPD reduced antagonist affinity 3- to 5-fold at NR2A-, NR2B- and NR2D-containing receptors, but had little effect on NR2C-containing receptors. In contrast, 4'-fluoro substitution of the biphenyl ring of PBPD selectively increased NR2A affinity. The aromatic rings of PBPD and PPDA increase antagonist affinity and appear to interact with a region of the NMDA receptor displaying subunit heterogeneity. PPDA is the most potent and selective NR2C/NR2D-preferring antagonist yet reported and thus may be useful in defining NR2C/NR2D function and developing related antagonists with improved NMDA receptor subtype selectivity. British Journal of Pharmacology (2004) 141, 508-516. doi:10.1038/sj.bjp.0705644

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References

Watanabe M, Inoue Y, Sakimura K, Mishina M . Distinct spatio-temporal distributions of the NMDA receptor channel subunit mRNAs in the brain. Ann N Y Acad Sci. 1993; 707:463-6. DOI: 10.1111/j.1749-6632.1993.tb38099.x. View

Laube B, Hirai H, Sturgess M, Betz H, Kuhse J . Molecular determinants of agonist discrimination by NMDA receptor subunits: analysis of the glutamate binding site on the NR2B subunit. Neuron. 1997; 18(3):493-503. DOI: 10.1016/s0896-6273(00)81249-0. View

Choi D . Antagonizing excitotoxicity: a therapeutic strategy for stroke?. Mt Sinai J Med. 1998; 65(2):133-8. View

Nakanishi S, Nakajima Y, Masu M, Ueda Y, Nakahara K, Watanabe D . Glutamate receptors: brain function and signal transduction. Brain Res Brain Res Rev. 1998; 26(2-3):230-5. DOI: 10.1016/s0165-0173(97)00033-7. View

Armstrong N, Sun Y, Chen G, Gouaux E . Structure of a glutamate-receptor ligand-binding core in complex with kainate. Nature. 1998; 395(6705):913-7. DOI: 10.1038/27692. View

Monaghan D, Andaloro V, Skifter D . Molecular determinants of NMDA receptor pharmacological diversity. Prog Brain Res. 1999; 116:171-90. DOI: 10.1016/s0079-6123(08)60437-9. View

Dingledine R, Borges K, Bowie D, Traynelis S . The glutamate receptor ion channels. Pharmacol Rev. 1999; 51(1):7-61. View

Binns K, Turner J, Salt T . Visual experience alters the molecular profile of NMDA-receptor-mediated sensory transmission. Eur J Neurosci. 1999; 11(3):1101-4. DOI: 10.1046/j.1460-9568.1999.00544.x. View

Christie J, Jane D, Monaghan D . Native N-methyl-D-aspartate receptors containing NR2A and NR2B subunits have pharmacologically distinct competitive antagonist binding sites. J Pharmacol Exp Ther. 2000; 292(3):1169-74. View

10.

Minami T, Matsumura S, Okuda-Ashitaka E, Shimamoto K, Sakimura K, Mishina M . Characterization of the glutamatergic system for induction and maintenance of allodynia. Brain Res. 2001; 895(1-2):178-85. DOI: 10.1016/s0006-8993(01)02069-8. View

11.

Auberson Y, Allgeier H, Bischoff S, Lingenhoehl K, Moretti R, Schmutz M . 5-Phosphonomethylquinoxalinediones as competitive NMDA receptor antagonists with a preference for the human 1A/2A, rather than 1A/2B receptor composition. Bioorg Med Chem Lett. 2002; 12(7):1099-102. DOI: 10.1016/s0960-894x(02)00074-4. View

12.

Hrabetova S, Serrano P, Blace N, Tse H, Skifter D, Jane D . Distinct NMDA receptor subpopulations contribute to long-term potentiation and long-term depression induction. J Neurosci. 2000; 20(12):RC81. PMC: 6772441. View

13.

Cheng Y, Prusoff W . Relationship between the inhibition constant (K1) and the concentration of inhibitor which causes 50 per cent inhibition (I50) of an enzymatic reaction. Biochem Pharmacol. 1973; 22(23):3099-108. DOI: 10.1016/0006-2952(73)90196-2. View

14.

Monaghan D, Cotman C . Identification and properties of N-methyl-D-aspartate receptors in rat brain synaptic plasma membranes. Proc Natl Acad Sci U S A. 1986; 83(19):7532-6. PMC: 386753. DOI: 10.1073/pnas.83.19.7532. View

15.

Monaghan D, Olverman H, Nguyen L, Watkins J, Cotman C . Two classes of N-methyl-D-aspartate recognition sites: differential distribution and differential regulation by glycine. Proc Natl Acad Sci U S A. 1988; 85(24):9836-40. PMC: 282876. DOI: 10.1073/pnas.85.24.9836. View

16.

Beaton J, Stemsrud K, Monaghan D . Identification of a novel N-methyl-D-aspartate receptor population in the rat medial thalamus. J Neurochem. 1992; 59(2):754-7. DOI: 10.1111/j.1471-4159.1992.tb09433.x. View

17.

Durand G, Gregor P, Zheng X, Bennett M, Uhl G, Zukin R . Cloning of an apparent splice variant of the rat N-methyl-D-aspartate receptor NMDAR1 with altered sensitivity to polyamines and activators of protein kinase C. Proc Natl Acad Sci U S A. 1992; 89(19):9359-63. PMC: 50126. DOI: 10.1073/pnas.89.19.9359. View

18.

Ikeda K, Nagasawa M, Mori H, Araki K, Sakimura K, Watanabe M . Cloning and expression of the epsilon 4 subunit of the NMDA receptor channel. FEBS Lett. 1992; 313(1):34-8. DOI: 10.1016/0014-5793(92)81178-o. View

19.

Harris N, Davies J . Cortically evoked excitatory synaptic transmission in the cat red nucleus is antagonised by D-AP5 but not by D-AP7. Brain Res. 1992; 594(1):176-80. DOI: 10.1016/0006-8993(92)91046-h. View

20.

Watanabe M, Inoue Y, Sakimura K, Mishina M . Developmental changes in distribution of NMDA receptor channel subunit mRNAs. Neuroreport. 1992; 3(12):1138-40. DOI: 10.1097/00001756-199212000-00027. View