Development of novel 4-aminopyridine derivatives as potential treatments for neurological injury and disease.
The amine position of the K+ channel blocker 4-aminopyridine was functionalized to form amide, carbamate and urea derivatives in an attempt to identify novel compounds which restore conduction in injured spinal cord. Eight derivatives were tested in vitro, using a double sucrose gap chamber, for the ability to restore conduction in isolated, injured guinea pig spinal cord. The methyl, ethyl and t-butyl carbamates of 4-aminopyridine induced an increase in the post injury compound action potential. The methyl and ethyl carbamates were further tested in an in vivo model of spinal cord injury. These results represent the first time that 4-aminopyridine has been derivatized without losing its ability to restore function in injured spinal cord tissue.
Smith
Daniel T
DT
Department of Industrial and Physical Pharmacy, Purdue University, 575 Stadium Mall Drive, West Lafayette, IN 47907, USA. dtsmith@pharmacy.purdue.edu
Shi
Riyi
R
Borgens
Richard B
RB
McBride
Jennifer M
JM
Jackson
Kevin
K
Byrn
Stephen R
SR
D015761:4-Aminopyridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000627:therapeutic use*; D000818:Animals; D002219:Carbamates / Q000138:chemical synthesis / Q000378:metabolism / Q000627:therapeutic use; D004195:Disease Models, Animal; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D005073:Evoked Potentials, Somatosensory / Q000187:drug effects; D006168:Guinea Pigs; D015394:Molecular Structure; D009431:Neural Conduction / Q000187:drug effects; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000503:physiopathology
D002219:Carbamates; D015761:4-Aminopyridine