Inhibition of the Vesicular Glutamate Transporter (VGLUT) with Congo Red Analogs: New Binding Insights.

The vesicular glutamate transporter (VGLUT) facilitates the uptake of glutamate (Glu) into neuronal vesicles. VGLUT has not yet been fully characterized pharmacologically but a body of work established that certain azo-dyes bearing two Glu isosteres via a linker were potent inhibitors. However, the distance between the isostere groups that convey potent inhibition has not been delineated. This report describes the synthesis and pharmacologic assessment of Congo Red analogs that contain one or two glutamate isostere or mimic groups; the latter varied in the interatomic distance and spacer properties to probe strategic binding interactions within VGLUT. The more potent inhibitors had two glutamate isosteres symmetrically linked to a central aromatic group and showed IC50 values ~ 0.3-2.0 µM at VGLUT. These compounds contained phenyl, diphenyl ether (PhOPh) or 1,2-diphenylethane as the linker connecting 4-aminonaphthalene sulfonic acid groups. A homology model for VGLUT2 using D-galactonate transporter (DgoT) to dock and identify R88, H199 and F219 as key protein interactions with Trypan Blue, Congo Red and selected potent analogs prepared and tested in this report.

High-resolution coronary MR angiography for evaluation of patients with anomalous coronary arteries: visualization of the intramural segment.

BACKGROUND: Anomalous origin of the coronary artery from the contralateral coronary sinus is a rare coronary anomaly associated with sudden death. The inter-arterial course is most closely associated with sudden death, but it has been suggested that the presence of an intramural segment of a right anomalous coronary is associated with more symptoms and therefore may be an important criterion for intervention in these patients. OBJECTIVE: To demonstrate that MR angiography can accurately determine the presence or absence of an intramural segment in an anomalous coronary artery. MATERIALS AND METHODS: All studies of children who underwent MR angiography for the evaluation of an anomalous coronary artery were retrospectively reviewed by two pediatric radiologists in consensus. Criteria for an intramural anomalous coronary artery were the presence of a small or slit-like ostium and the relative smaller size of the proximal intramural portion of the coronary artery in relation to the more distal epicardial coronary artery. The anomalous coronary artery was classified as not intramural if these two findings were absent. These findings were correlated with operative reports confirming the presence or absence of an intramural segment. RESULTS: Twelve patients (86%) met MR angiography criteria for the presence of an intramural course. Only 2 patients (14%) met MR angiography criteria for a non-intramural course. When correlating with intraoperative findings, MR angiography was successful in distinguishing between intramural and non-intramural anomalous coronary arteries in all cases (P = 0.01). CONCLUSION: MR angiography may be able to reliably identify the intramural segment of an anomalous coronary artery in older children using the imaging criteria of a small or slit-like ostium and relative decrease in size of the proximal portion of the anomalous coronary artery compared to the distal portion of the anomalous coronary artery. Determining the presence of the intramural segment may help with surgical planning and may be an important criterion for the determination of intervention in patients with inter-arterial anomalous right coronary arteries.

Chemoenzymatic resolution of rac-malathion.

Malathion, diethyl 2-[(dimethoxyphosphorothioyl)sulfanyl]butanedioate, is an organophosphate used to control insect pests. Malathion contains a diethyl succinate moiety that is a known functional group susceptible to desymmetrizing enzymes such as esterases that selectively react with a single enantiomer. Purified rac-malathion was subjected to hydrolysis at the diethyl succinate moiety of malathion under various conditions using wild type pig liver esterase to form (S)-malathion (12 % ee) and ~ 3:2 mixture of α- and ß-monoacids of (R)-malathion. Technical malathion could not be enriched due to the presence of esterase inhibitors. Further investigation of this resolution using a panel of six PLE isoenzymes also demonstrated formation of (S)-malathion, however, an improvement of up to 56 % ee was obtained.