This proposal presents an integrated approach involving synthesis, molecular computer simulations, conformational analyses and biological studies for the design and synthesis of novel molecules with somatostatin activity. Our target structures incorporate enantioselective beta-methylated amino acids, peptoids and unnatural amino acids to improve selectivity and potency. In addition computer simulated models of the hsst2, hsst3 and hsst5 receptors have provided insight into the nature of ligand-receptor interactions and allowed us to identify specific binding sites for receptor subtype selectivity. From these leads, we designed and synthesized somatostatin analogs with high potency and high selectivity at hsst3 (Pro1-c[Cys2-Phe -D-Trp4-Lys4-Val6-Cys7]-NH2- and hsst5 (Arg1-c[Cys2 -Tyr3 -D-Trp4-Lys5-Val6Cys7] -Lys8-NH2). We will now refine the simulated receptor binding sites and synthesize new highly selective and potent somatostatin analogs into which we will incorporate special building blocks including naphthylalanine, p-fluorophenylalanine, beta-hydroxyvaline, and Ngamma-methyl-Ngamma-aminoethyl-diaminobutyric acid (MAEDAB) to enhance selectivity and potency. It is also our goal to design somatostatin analogs which are based on peptidomimetic and nonpeptide scaffolds. For this purpose we will synthesize cyclic peptidomimetics which consist of the pharmacophore unit D-Trp-Lys linked to nonpeptide-turn mimetics such as the Nowick urea and Kelly dibenzylfuran scaffolds.. For nonpeptide analogs we will utilize N-alkyl-2-alkyl-2,3-dihydro-4pyridones as a scaffold on which we will array somatostatin pharmacophores. The pyridone templates will be prepared using novel Diels Alder-type chemistry based on reactions of modified Danishefsky dienes with specially prepared imines. In a related study, we will synthesize and probe anticancer activity of a new class of somatostatin analogs conjugated to cobalt complexes. Through our collaborators, binding studies and in vitro and in vivo functional bioassays will be carried out.