Numerous behavioral studies indicate that dopamine transporter (DAT) inhibitors and metabotropic glutamate receptor 5 (mGlu5) negative allosteric modulators (NAMs) possess promising anti-addiction therapeutic properties. However, the lack of human DAT (hDAT) and mGlu5 X-ray crystal structures makes it difficult to understand how these promising anti-addiction compounds interact with their major drug targets at the molecular level. This knowledge gap represents an important problem towards rationally designing new therapeutics for numerous addiction disorders. The objective of this research was to develop irreversible chemical probes based on select DAT inhibitors and mGlu5 NAMs in order to map the corresponding binding sites and poses of these compounds within their major drug targets. The central hypothesis was that these compounds could be derivatized, without significant loss in pharmacological activity, with a functional group capable of forming a covalent bond to their target protein and, if necessary, a tag functional group. These probes would then allow proteomic experiments to be coupled with computational modeling in order to directly map the ligand-binding sites of these promising anti-addiction compounds within their target proteins. The central hypothesis was tested by pursuing two specific aims: 1) identification of non-tropane DAT inhibitor photoprobes suitable for DAT structure-function studies, and 2) identification of irreversible mGlu5 NAM ligands as chemical probes suitable for mGlu5 structure-function studies. Under the first aim, methylphenidate (MP) and GBR-12909 as non-tropane DAT inhibitors were structurally modified to contain a photoreactive group (e.g., aryl azide, benzophenone) and a tag (e.g., 125I, terminal alkyne, aliphatic azide). These compounds were then subjected to DAT pharmacological evaluation in order to identify suitable candidates for DAT structure-function studies. Under the second aim, thiazole- and pyridine-based mGlu5 NAMs were structurally modified to contain either a photoreactive group (e.g., aryl azide, benzophenone) or an affinity labeling group (e.g., methanethiosulfonate, maleimide) and a tag (e.g., 125I, terminal alkyne, aliphatic azide). These compounds were then subjected to mGlu5 pharmacological evaluation in order to identify suitable chemical probe candidates for mGlu5 structure-function studies. At present, several irreversible chemical probes from these specific aims have advanced to the proteomics stage of the experimental research strategy. / Mylan School of Pharmacy and the Graduate School of Pharmaceutical Sciences; / Medicinal Chemistry / PhD; / Dissertation;

<p>The specific objectives of this study were to investigate whether Artemisia Afra, Leonotis leonorous and Mentha Longiflora have PDE 4 inhibitory activity, to determine and compare the levels of the total phenolic compunds , total and individual flavanoids, especially luteolin and hesperetin, in the three plants and finally, to determine if there was a correlation between the PDE inhibitory activity and the levels of flavanoids or phenolic compounds in the plants. It was hypothesized that the plants with higher levels of total flavonoid and/or aglycone luteolin and/or hesperetin had higher PDE inhibitory activity.</p>

<p>&quot / An aqueous extract prepared from the leaves and smaller stems of Leonotis leonorus was used to investigate the potential effects on certain cardiovascular parameters such as left ventricular systonic pressure, end-diastolic pressure, developed pressure, heart rate, cardiac work and coronary perfusion pressure in isolated rat hearts...&quot / </p>

Farmers generally collect fresh plant materials from the wild for ethnoveterinary uses. They are encouraged to harvest with caution and dry or cultivate important materials in order to protect the biodiversity. These recommendations are not validated scientifically. The microplate method for minimum inhibitory concentration (MIC) determination was used to compare wild with cultivated, and fresh with dry plant materials. The MIC values obtained ranged from 1.25 to 0.01 mg/ml. MIC values ≤0.3 mg/ml were considered as cut off point between effective and none effective inhibition. The multilevel linear models (hierarchical linear models), both unadjusted and adjusted models were employed. The plant (name) was considered as level-2 or higher level, while the actual observation was level-1 or lower level. The crude estimates of the odds ratio indicated that wild is significantly 0.57 times less likely than garden to yield MIC values of more than 0.3 mg/ml (p-value = 0.005). Also, fresh are about 4.195 times more likely than dry to yield MIC scores of more than 0.3 mg/ml (p-value < 0.001). Adjusting for conditions “dry and fresh”, microbe and solvent; wild is significantly 0.52 times less likely than garden to yield MIC values of more than 0.3 mg/ml (p-value = 0.003). On the other hand, when adjusting for “wild or garden”, type of solvents and type of microbes; fresh is significantly 4.202 times more likely than dry to yield MIC values of more than 0.3 mg/ml (p-value < 0.001). These results partially support farmers claiming that wild plant materials are more potent than the grown ones. On the contrary, the results are in favour of drying plant materials.

It is believed that early humans had knowledge of how to use traditional medicinal plants, but the knowledge has been partially lost as society underwent various changes leading to new civilizations. The aim of this study was to isolate and identify natural product constituents from Tulbaghia Alliacea. There has not yet been any scientifically conducted investigation on the plant. Tulbaghia Alliacea is used for fever and colds, asthma, pulmonary tuberculosis and stomach problems.

<p>&quot / An aqueous extract prepared from the leaves and smaller stems of Leonotis leonorus was used to investigate the potential effects on certain cardiovascular parameters such as left ventricular systonic pressure, end-diastolic pressure, developed pressure, heart rate, cardiac work and coronary perfusion pressure in isolated rat hearts...&quot / </p>

<p>The specific objectives of this study were to investigate whether Artemisia Afra, Leonotis leonorous and Mentha Longiflora have PDE 4 inhibitory activity, to determine and compare the levels of the total phenolic compunds , total and individual flavanoids, especially luteolin and hesperetin, in the three plants and finally, to determine if there was a correlation between the PDE inhibitory activity and the levels of flavanoids or phenolic compounds in the plants. It was hypothesized that the plants with higher levels of total flavonoid and/or aglycone luteolin and/or hesperetin had higher PDE inhibitory activity.</p>

It is believed that early humans had knowledge of how to use traditional medicinal plants, but the knowledge has been partially lost as society underwent various changes leading to new civilizations. The aim of this study was to isolate and identify natural product constituents from Tulbaghia Alliacea. There has not yet been any scientifically conducted investigation on the plant. Tulbaghia Alliacea is used for fever and colds, asthma, pulmonary tuberculosis and stomach problems.

Thesis (MPharm(Department of Pharmacology))--University of the Western Cape, 2007. / Includes Bibliographis references (leaves 79-86).

Thesis (M. Phil.)--University of Hong Kong, 2010. / Includes bibliographical references (leaves 101-110). Also available in print.