| dc.contributor.author | Carter, Michael D. | en_US |
| dc.date.accessioned | 2014-10-21T12:35:11Z | |
| dc.date.available | 2006 | |
| dc.date.issued | 2006 | en_US |
| dc.identifier.other | AAINR16696 | en_US |
| dc.identifier.uri | http://hdl.handle.net/10222/54787 | |
| dc.description | Existing treatments for Alzheimer's disease (AD) fail to address the underlying pathology of the disease, instead providing symptomatic relief which is often short-lived. Consequently, progression of the disease is unrelenting, leading to a continual decrease in cognitive abilities which eventually results in death. | en_US |
| dc.description | In an effort to develop a more effective treatment for AD, a rational drug design\strategy was implemented. After considering the biochemistry of the disease, the region comprising residues 11 to 16 of the Alzheimer peptide, amyloid-beta (Abeta), having the sequence Glu-Val-His-His-Gln-Lys (or EVHHQK using the single-letter codes for amino acids), was chosen as the target for drug design. Molecules were designed to bind to this region by forming either two cation-pi interactions or one cation-pi interaction and one salt bridge at two of the three basic residues contained in the region (i.e. His and Lys residues). An alternative group of compounds was intended to bind to one of the two basic His residues and to the anionic sidechain of Glu. In both cases, binding was anticipated to interrupt Abeta-Abeta interactions and thereby inhibit assembly of the peptide into toxic aggregates. | en_US |
| dc.description | Molecular modeling revealed that, among 11 common aromatic groups studied, indole formed the strongest cation-pi interactions with the cationic sidechains of His and Lys. This recommended its incorporation into molecules designed to bind to the EVHHQK region of Abeta. A total of 56 bis-indole and indole-anionic molecules were thus synthesized, with varying indole-indole and indole-anion separation. | en_US |
| dc.description | Biological testing of the molecules in a dye-binding Abeta aggregation assay revealed activity for a number of the synthesized compounds. These not only inhibited the aggregation of "fresh" Abeta but also disassembled pre-formed aggregates. Circular dichroism analysis supported these results; compounds incubated with Abeta inhibited the time-dependent shift in the peptide's secondary structure from random coil to beta-sheet. | en_US |
| dc.description | Finally, a clinical trial of the indole-anionic compound L-tryptophan was carried out in people with mild to moderate AD. People receiving L-tryptophan outperformed those taking placebo on a number of cognitive tests, suggesting the compound may have application in treating AD. | en_US |
| dc.description | Thesis (Ph.D.)--Dalhousie University (Canada), 2006. | en_US |
| dc.language | eng | en_US |
| dc.publisher | Dalhousie University | en_US |
| dc.publisher | | en_US |
| dc.subject | Health Sciences, Pharmacology. | en_US |
| dc.subject | Chemistry, Organic. | en_US |
| dc.subject | Chemistry, Pharmaceutical. | en_US |
| dc.title | Design, synthesis and evaluation of new chemical entities for the treatment of Alzheimer's disease. | en_US |
| dc.type | text | en_US |
| dc.contributor.degree | Ph.D. | en_US |
