Part 1. The complex folded structures associated with RNA allow for specific protein-RNA interactions and also create binding sites for small molecules. Developing organic molecules that can bind RNA with high affinity and specificity is a challenge that must be overcome for RNA to be considered a viable drug target. Polyamines with different side chains were synthesized to test for binding affinity and specificity to TAR and RRE of HIV. Binding interactions between polyamines and RNAs were examined using fluorescence assays and two foot-printing assays based on terbium-induced cleavage and magnesium-catalyzed cleavage at high pH. Binding constants and specificity were highly dependent on the side chains of the polyamines, demonstrating that this class of molecules is a promising starting point for the development of highly selective RNA binding ligands. Part 2. The overproduction of nitric oxide (NO) by neuronal nitric oxide synthase (nNOS) has been implicated in a variety of neurological diseases, including Parkinson's and neuronal damage due to hypoxic conditions such as stroke. Inhibition of nNOS could have therapeutic benefit, but must be achieved without inhibition of the endothelial isoform (eNOS), as that would lead to hypertension. Using computer modeling of drug-like fragments in the crystal structures of nNOS and eNOS, a class of highly selective and potent nNOS inhibitors was discovered. Modification of the structures of these lead compounds to optimize for pharmacological properties without sacrificing potency and selectivity was carried out. Replacing a 2- aminopyridine group in the leads with aminothiazoles resulted in a dramatic loss in potency. The replacement of secondary amines with ether and amide linkages generally reduced potency; however, in one case an ether-containing compound was as potent and selective as the best lead compound. Brain uptake studies in mice proved that the modification did have a beneficial effect on the amount of compound that crosses the blood brain barrier. The neutralization of other secondary amines in the molecule with amides and carbamates was carried out to investigate whether a prodrug approach could further increase brain uptake. In all cases, however, the capping of the secondary amine had no beneficial effect on brain uptake

Last modified

• 06/26/2018

Creator

• Graham R Lawton

DOI

• https://doi.org/10.21985/N2V13R

Subject

• Chemistry

Keyword

• Chemistry

Date created

• 2007-05-03

Resource type

• Dissertation

Rights statement

• In Copyright