The vesicular glutamate transport (VGLUT) system selectively mediates the uptake of L-glutamate into synaptic vesicles. Uptake is linked to an H+-ATPase that provides coupling among ATP hydrolysis, an electrochemical proton gradient, and glutamate transport. Substituted quinoline-2,4-dicarboxylic acids (QDCs), prepared by condensation of dimethyl ketoglutaconate (DKG) with substituted anilines and subsequent hydrolysis, were investigated as potential VGLUT inhibitors in synaptic vesicles. A brief panel of substituted QDCs was previously reported (Carrigan et al. Bioorg. Med. Chem. Lett. 1999, 9, 2607-2612)(1) and showed that certain substituents led to more potent competitive inhibitors of VGLUT. Using these compounds as leads, an expanded series of QDC analogues were prepared either by condensation of DKG with novel anilines or via aryl-coupling (Suzuki or Heck) to dimethyl 6-bromoquinolinedicarboxylate. From the panel of almost 50 substituted QDCs tested as inhibitors of the VGLUT system, the 6-PhCH=CH-QDC (K(i) = 167 microM), 6-PhCH2CH2-QDC (K(i) = 143 microM), 6-(4'-phenylstyryl)-QDC (K(i) = 64 microM), and 6-biphenyl-4-yl-QDC (K(i) = 41 microM) were found to be the most potent blockers. A preliminary assessment of the key elements needed for binding to the VGLUT protein based on the structure-activity relationships for the panel of substituted QDCs is discussed herein. The substituted QDCs represent the first synthetically derived VGLUT inhibitors and are promising templates for the development of selective transporter inhibitors.

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Cell therapies have the potential to revolutionize the treatment of spinal cord injury. Basic research has progressed significantly in recent years, with a plethora of cell types now reaching early-phase human clinical trials, offering new strategies to repair the spinal cord. However, despite initial enthusiasm for preclinical and early-phase clinical trials, there has been a notable hiatus in the translation of cell therapies to routine clinical practice. Here, we review cell therapies that have reached clinical trials for spinal cord injury, providing a snapshot of all registered human trials and a summary of all published studies. Of registered trials, the majority have used autologous cells and approximately a third have been government funded, a third industry sponsored, and a third funded by university or healthcare systems. A total of 37 cell therapy trials have been published, primarily using stem cells, although a smaller number have used Schwann cells or olfactory ensheathing cells. Significant challenges remain for cell therapy trials in this area, including achieving stringent regulatory standards, ensuring appropriately powered efficacy trials, and establishing sustainable long-term funding. However, cell therapies hold great promise for human spinal cord repair and future trials must continue to capitalize on the exciting developments emerging from preclinical studies.