Synthesis and pharmacology of N1-substituted piperazine-2,3-dicarboxylic acid derivatives acting as NMDA receptor antagonists

Richard M. Morley, Heong Wai Tse, Bihua Feng, Jacqueline C. Miller, Daniel T. Monaghan, David E. Jane

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

The binding site for competitive NMDA receptor antagonists is on the NR2 subunit, of which there are four types (NR2A-D). Typical antagonists such as (R)-AP5 have a subunit selectivity of NR2A > NR2B > NR2C > NR2D. The competitive NMDA receptor antagonist (2R*,3S*)-(1-biphenylyl-4- carbonyl)piperazine-2,3-dicarboxylic acid (PBPD, 16b) displays an unusual selectivity with improved relative affinity for NR2C and NR2D vs NR2A and NR2B. Analogues of 16b bearing aroyl or aryl substituents attached to the N 1 position of piperazine-2,3-dicarboxylic acid have been synthesized to probe the structural requirements for NR2C/NR2D selectivity. A phenanthrenyl-2-carbonyl analogue, 16e, had >60-fold higher affinity for NR2C and NR2D and showed 3-5-fold selectivity for NR2C/NR2D vs NR2A/NR2B. The phenanthrenyl-3-carbonyl analogue (16f) was less potent but more selective, having 5- and 7-fold selectivity for NR2D vs NR2A and NR2B, respectively. Thus, antagonists bearing bulky hydrophobic residues have a different NR2 subunit selectivity than that of typical antagonists.

Original languageEnglish (US)
Pages (from-to)2627-2637
Number of pages11
JournalJournal of Medicinal Chemistry
Volume48
Issue number7
DOIs
StatePublished - Apr 7 2005

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Bearings (structural)
Dicarboxylic Acids
N-Methyl-D-Aspartate Receptors
Pharmacology
Derivatives
Binding Sites
piperazine

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Synthesis and pharmacology of N1-substituted piperazine-2,3-dicarboxylic acid derivatives acting as NMDA receptor antagonists. / Morley, Richard M.; Tse, Heong Wai; Feng, Bihua; Miller, Jacqueline C.; Monaghan, Daniel T.; Jane, David E.

In: Journal of Medicinal Chemistry, Vol. 48, No. 7, 07.04.2005, p. 2627-2637.

Research output: Contribution to journalArticle

Morley, Richard M. ; Tse, Heong Wai ; Feng, Bihua ; Miller, Jacqueline C. ; Monaghan, Daniel T. ; Jane, David E. / Synthesis and pharmacology of N1-substituted piperazine-2,3-dicarboxylic acid derivatives acting as NMDA receptor antagonists. In: Journal of Medicinal Chemistry. 2005 ; Vol. 48, No. 7. pp. 2627-2637.
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