The design and synthesis of novel ligands for the somatostatin and NK1 receptors incorporating the beta-D-glucoside scaffold and related mimetics of peptidal beta-turns.

摘要

This thesis describes the design and synthesis of beta-D-glycosides and related scaffolds as effective probes to unravel ligand/receptor interactions. Chapter 1 provides the background of somatostatin (SRIF), in conjunction with an overview of the peptidomimetics program at the University of Pennsylvania since 1987.; Chapter 2 discusses the exploitation of the inherent radially symmetric property of glycosides in lead discovery and lead optimization. Further structure-activity relationships of lead (-)-2--5 resulted in the discovery of a highly potent NK1 ligand (-)-2--36 with an IC 50 of 3 nM.*; Chapter 3 conveys the extension of the concept of electrostatic potential of aromatic rings, which distinguishes the benzene and the indole rings from the pyridine and pyrazine rings. The synthesis of four bioactive analogues of the somatostatin (SRIF) mimetic, beta-D-glucoside (+)- 1--1, in which the Cl indole side chain is replaced with indole surrogates, has been achieved. These congeners, possessing the naphthyl, benzothiophene, benzyl, and benzofuran substituents, were predicted to satisfy the electrostatic potential requirements of the tryptophan binding pocket of SRIF.*; The final chapter describes the exploitation of new scaffolds toward the understanding of their role in ligand-receptor interaction. The investigation of other scaffolds for beta-turn mimicry has guided us in unraveling the role of the sugar core in ligand-receptor binding. For example, carbocycle (+)-4--1 was designed to probe the role of the pyranose oxygen in binding. Catechol 4--2 was also explored as a simpler planar scaffold to expose the significance, if any, of the stereochemical disposition of the critical Trp8 and Lys9 side chains of SRIF.*; *Please refer to dissertation for diagrams.