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-[ 3 H]-glutamate binding assays and at recombinant receptors expressed in Xenopus oocytes. 2 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. 3 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. 4 Replacement of the biphenyl group of PBPD with a 9-oxofluorene ring system resulted in small changes in receptor affinity and subtype selectivity. 5 2 0 -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 0 -fluoro substitution of the biphenyl ring of PBPD selectively increased NR2A affinity. 6 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.

The spectroscopic properties of solvent soluble derivatives of Brooker's simple merocyanine 4-[(1-methyl-4(1H)-pyridinylidene)ethylidene]-2,5-cyclohexadien-1-one, which can in principle exist in two distinct canonical forms, have been assessed both experimentally and theoretically using molecular orbital methods. 1 H and 13 C NMR evidence in a range of solvents suggests that the merocyanine exists as a resonance hybrid which is weighted toward the zwitterion even in solvents of low dielectric constants. In protic solvents, the large hypsochromic shift observed for the merocyanine in the visible region arises from both a dielectric effect and a hydrogen bonding effect. Theoretically, the PM3/COSMO method gives a reasonable account of the structure and spectroscopic shifts of the merocyanine in aprotic solvents. The large shifts observed arise because solvents with large dielectric constants have a much greater stabilizing effect on the more polar ground state of the merocyanine than they do on the first excited state. While the same method predicts stable hydrogen-bonded structures for a dihydrate and hexahydrate, it is unable to reproduce the known hypsochromic shift for these solvated species. In contrast, a version of the CNDO/S method does predict the correct trends on hydration though the magnitude of the effect is less than that found experimentally.Recent studies have strongly suggested that one of the main factors which contribute to the large solvatochromic shift is a

The natural product willardiine (8) is an AMPA receptor agonist while 5-iodowillardiine (10) is a selective kainate receptor agonist. In an attempt to produce antagonists of kainate and AMPA receptors analogues of willardiine with substituents at the N3 position of the uracil ring were synthesized. The N3-4-carboxybenzyl substituted analogue (38c) was found to be equipotent at AMPA and GLUK5-containing kainate receptors in the neonatal rat spinal cord. The N3-2-carboxybenzyl substituted analogue (38a) proved to be a potent and selective GLUK5 subunit containing kainate receptor antagonist when tested on native rat and human recombinant AMPA and kainate receptor subtypes. The GLUK5 kainate receptor antagonist activity was found to reside in the S enantiomer (44a) whereas the R enantiomer (44b) was almost inactive. 5-Iodo substitution of the uracil ring of 44a gave 45, which was found to have enhanced potency and selectivity for GLUK5.