Edward C. R. Smith

5,7-Dichlorokynurenic acid, a potent and selective competitive antagonist of the glycine site on NMDA receptors

Fourteen substituted derivatives of kynurenic acid were compared for their ability to block ionic currents evoked by N-methyl-D-aspartate (NMDA) plus glycine, or kainate, in voltage-clamped Xenopus oocytes injected with rat brain messenger RNA. Among these analogues there was an excellent correlation between the Ki for displacing [3H]glycine binding to rat brain membranes, and the ability to inhibit ionic currents evoked by glycine/NMDA in Xenopus oocytes. In the oocyte 5,7-dichlorokynurenic acid (5,7-DCK) was a competitive blocker of the glycine recognition site on NMDA receptors, and was more potent (KB 65 nM in Schild analysis) and selective (509-fold more potent vs glycine than kainate) than the prototype glycine antagonist, 7-chlorokynurenic acid, 5,7-DCK also reduced NMDA-induced neuron injury in rat cortical cell cultures.

Structure-activity relationships of a series of 1-substituted-4-methylbenzimidazole neuropeptide Y-1 receptor antagonists.

The characterization of a novel series of NPY-1 receptor antagonists derived from the 4-methylbenzimidazole 4 is described. Appropriate substitution on the piperidyl nitrogen of 4 led to systematic increases in Y-1 receptor affinity, to approximately 50-fold, and to the discovery of the importance of a second basic substituent.

Synthesis and 5α-reductase inhibitory activity of 8-substituted benzo[ƒ]quinolinones derived from palladium mediated coupling reactions

Benzoquinolinones have been shown to be potent, selective inhibitors of the Type I 5 alpha-reductase enzyme, which is responsible for the production of dihydrotestosterone from testosterone localized in the scalp. In an effort to identify compounds that demonstrate inhibition of both 5 alpha-reductase isozymes, we have employed 8-bromobenzoquinolinone as an advanced intermediate for participation in a variety of palladium mediated carbon-carbon bond forming reactions. By varying the 8-substituent it is possible to alter the selectivity profile of the series.

Structure-activity relationships of a series of glycine antagonists related to 5,7-dichlorokynurenic acid and 3-(2-carboxy-6-chloroindol-3-yl)acetic acid

Abstract A series of 3-substituted acetic and propanoic acid derivatives of 5,7-dichlorokynurenic acid were prepared and evaluated as antagonists of the glycine site on the NMDA receptor complex. They were found to possess reduced affinity for the glycine site relative to 5,7-dichlorokynurenic acid and the analogous 2-carboxyindole-3-acetic acid series of glycine antagonists.

Changes in ascorbate, glutathione and α-tocopherol concentrations in the brain regions during normal development and moderate hypoglycemia in rats

Ascorbate, glutathione and α-tocopherol are the major low molecular weight antioxidants in the brain. The simultaneous changes in these compounds during normal development, and under a pro-oxidant condition are poorly understood. Ascorbate, glutathione and α-tocopherol concentrations in the olfactory bulb, cerebral cortex, hippocampus, striatum, hypothalamus, midbrain, cerebellum, pons and medulla oblongata were determined in postnatal day (P) 7, P14 and P60 male rats. A separate group of P14 and P60 rats were subjected to acute hypoglycemia, a pro-oxidant condition, prior to tissue collection. The concentrations of all three antioxidants were 100-600% higher in the brain regions at P7 and P14, relative to P60. The neuron-rich anterior brain regions (cerebral cortex and hippocampus) had higher concentrations of all three antioxidants than the myelin-rich posterior regions (pons and medulla oblongata) at P14 and P60. Hypoglycemia had a differential effect on the antioxidants. Glutathione was decreased at both P14 and P60. However, the decrease was localized at P14 and global at P60. Hypoglycemia had no effect on ascorbate and α-tocopherol at either age. Higher antioxidant concentrations in the developing brain may reflect the risk of oxidant stress during the early postnatal period and explain the relative resistance to oxidant-mediated injury at this age.