Conformational studies of biologically significant peptide structures (Drug design)

In this dissertation, the use of high resolution NMR and molecular modeling is illustrated for the examination of the structures based on peptide-hormones and a peptide fragment of the κ opioid receptor. Utilizing a “domain approach”, the secondary structural features of the extracellular loop II (ECL II) of the κ opioid receptor have been deduced and incorporated into a homology model of the receptor. Furthermore, the conformational preferences of many biologically active analogs have been studied. The structure-activity relationships were established to assist in the design and synthesis of new potent and selective analogs of pharmacological interest.; The binding profile of ligands to the κ opioid receptor is relatively unique among the opioid receptors, while those of the μ and δ receptors are similar to each other. The ECL II appears to be the binding domain for κ selective peptide ligands. Therefore, we synthesized a peptide mimic of the ECL II. Our results proposed an amphiphilic helical domain of the ECL II, which interacts with the κ-selective endogenous ligand Dyn A.; Integrin receptors are cell surface receptors. We employed transferred NOE experiments to study the bound conformation of an antagonist of the α ₅β₁ integrin receptor, which is involved in tumor metastasis. Our results shed light on the important phamacophore for ligands binding to the isolated and reconstituted α₅β₁ receptor. These results will facilitate the design of novel α₅β ₁ integrin antagonists to produce new cancer therapeutics.; The synthetic somatostatin analog sandostatin has been studied extensively because of its therapeutic utility in the treatment of acromegaly and cancers related to this disease. Conformational analyses of the series of sandostatin analogs containing stereoisomeric modifications at positions 6 or 8 were carried out. These studies offer new insight into the structural requirements for binding to somatostatin receptors.; The present generation of opiate analgesics, such as morphine can cause undesirable side effects through activity at the μ receptor. The research efforts in our group focus on the design and synthesis of potent ligands that bind to either δ or κ receptors. A series of dynorphin A (1-11) analogs substituted with Pro and D-Pro in position 2 or 3, were synthesized and produced highly κ selective antagonists. The conformational analyses have found two isomeric forms for each proline analog and the tendency for these analogs to form turn-like structures around proline residues.; In addition, we are continuing our efforts to design and synthesize highly δ-selective analogs. The conformational and biological properties of families of enkephalin analogs: N-methyl-amine bridged and dimethylated lanthionine (monosulfide bridge) analogs were studied. Furthermore, the dimethylated dermorphin/deltorphin analogs were synthesized as part of our extended efforts to make dimethylated building blocks. Conformational analyses of these analogs indicate that the dimethylations at the second position of the cyclic opioid analogs play a crucial role in modulating selectivity toward either the δ or μ receptor. On the other hand, the modifications of the bridge region of the cyclic opioid analogs are well tolerated by the opioid receptors.