? ? Potassium channel blockade has been identified as a promising means of restoring behavioral functioning secondary to spinal cord injury (SCI). However, the recent failure of the K+ channel blocker 4-aminpyridine (4-AP) in Phase III clinical trials as a treatment of SCI highlights the need for additional leads which restore conduction in injured spinal cord. A search of the literature indicates that there has been essentially no attempted """"""""lead optimization"""""""" of the 4-AP pharmacophore, a standard practice in the pharmaceutical industry. The current application proposes to identify new compounds that reverse SCI induced conduction block and to quantify their restorative effects in vitro. Successfully completing these aims will further the long term goal of developing novel treatments of chronic SCI.
The specific aims outlined within this proposal include the synthesis of 4-AP - like molecules followed by in vitro screening of the derivatives to observe and then quantify their ability to restore conduction in isolated, injured guinea pig spinal cords. Twenty-five molecules have been rationally identified as being likely to reverse conduction block. Sufficient quantities of each target will be obtained through either purchase or synthesis. To aid further developmental efforts, a qualitative assessment of water stability and a quantification of water solubility for each compound will be made at the time of synthesis. In vitro testing of each compound will be done using a double sucrose gap isolation chamber in order to determine its ability to restore the compound action potential in mechanically injured guinea pig spinal cords. Compounds that demonstrate the ability to restore conduction will have a dose response curve constructed in order to quantify the results and to identify the concentration of maximum response. The results generated by the proposed study will serve as the foundation for additional pre-clinical development that will advance novel treatments of chronic SCI toward the human clinic. ? ?
| Leung, Gary; Sun, Wenjing; Brookes, Sarah et al. (2011) Potassium channel blocker, 4-aminopyridine-3-methanol, restores axonal conduction in spinal cord of an animal model of multiple sclerosis. Exp Neurol 227:232-5 |
| Shi, Riyi; Sun, Wenjing (2011) Potassium channel blockers as an effective treatment to restore impulse conduction in injured axons. Neurosci Bull 27:36-44 |
