Stroke is the 3rd leading cause of death in the United States. For this reason, it has become our goal to find a drug that is capable of reestablishing intracellular and extracellular Ca+2 flux upon direct binding to the sigma receptor, which can be delivered easily and efficiently. Our active research focuses the development of guanidine analogues that can serve as therapeutic drugs which target sigma 1 and sigma 2 receptors having a direct effect on Ca+2 levels on the cell. The use of symmetrical guanidine analogues such as N,N'-di- o-tolyl guanidine (o-DTG) as therapeutic drugs for ischemic stroke, is promising due to the fact that neuronal cells can restore the proper blood flow and block Ca+2 flux into the cell. Our main objective is to be able to develop a cost efficient, mild reaction methodology that affords access to guanidine analogues. The synthetic design of the guanidine analogues has been accomplished using copper-catalyzed cross-coupling diarylation reaction. This methodology employs a non-expensive guanidine salt and substituted aryl iodides along with N,N'-diethylsalicylamides as the key ligand in this strategy. Similar methodology was employed for the synthesis of monoarylated amidines employing ligand-free conditions for the copper-catalyzed cross-coupling reaction. Moreover, efforts to find alternative methodologies to access other sigma receptor ligands were accomplished. A new method to create N,N'-disubstituted carbamides employed HATU as a peptide coupling agent allowing for the formation of carbamides using the inexpensive guanidine nitrate and carboxylic acids as starting materials.
Studies on the sigma response of the cortical neuron cell were conducted upon completion of the analogue design. Moreover, it was discovered that N,N'-di-p-bromophenyl guanidine (p-BrDPhG) gave a higher Ca+2 inhibition than N,N'-di- o-tolyl guanidine (o-DTG). Experimental studies, such as the middle cerebral occlusion were conducted on rats and subsequent injections of the p-BrDPhG at 24, 48, and 72 hours' time marks. When compared to o-DTG, it was found that p-BrDPhG is better at reducing the ischemic volume on the brain size.
|Advisor:||Antilla, Jon C.|
|Commitee:||Baker, Bill, Bisht, Kirpal, Cuevas, Javier, Zhang, Peter|
|School:||University of South Florida|
|School Location:||United States -- Florida|
|Source:||DAI-B 73/03, Dissertation Abstracts International|
|Keywords:||Amidinylation, Arylation, Carbamides, Copper, Guanidinylation, Peptide coupling, Post-stroke, Sigma receptor ligands|
Copyright in each Dissertation and Thesis is retained by the author. All Rights Reserved
The supplemental file or files you are about to download were provided to ProQuest by the author as part of a
dissertation or thesis. The supplemental files are provided "AS IS" without warranty. ProQuest is not responsible for the
content, format or impact on the supplemental file(s) on our system. in some cases, the file type may be unknown or
may be a .exe file. We recommend caution as you open such files.
Copyright of the original materials contained in the supplemental file is retained by the author and your access to the
supplemental files is subject to the ProQuest Terms and Conditions of use.
Depending on the size of the file(s) you are downloading, the system may take some time to download them. Please be