title: Synthesis and pharmacology of N1-substituted piperazine-2,3-dicarboxylic acid derivatives acting as NMDA receptor antagonists.
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.
authors.affiliation: Department of Pharmacology, MRC Centre for Synaptic Plasticity, School of Medical Sciences, University Walk, University of Bristol, Bristol, BS8 1TD, UK.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Morley
authors.forename: Heong-Wai
authors.initials: HW
authors.lastname: Tse
authors.forename: Bihua
authors.initials: B
authors.lastname: Feng
authors.forename: Jacqueline C
authors.initials: JC
authors.lastname: Miller
authors.forename: Daniel T
authors.initials: DT
authors.lastname: Monaghan
authors.forename: David E
authors.initials: DE
authors.lastname: Jane
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D015394:Molecular Structure; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D009865:Oocytes / Q000187:drug effects / Q000502:physiology; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021122:Protein Subunits / Q000037:antagonists & inhibitors / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013116:Spinal Cord / Q000166:cytology; D013237:Stereoisomerism; D014982:Xenopus laevis
chemical_list: C473649:NR1A NMDA receptor, rat; C120997:NR2A NMDA receptor; D010879:Piperazines; D021122:Protein Subunits; D016194:Receptors, N-Methyl-D-Aspartate; D011994:Recombinant Proteins