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