MAIN CHAIN AND SIDE-CHAIN CHIRAL METHYLATED SOMATOSTATIN ANALOGS - SYNTHESES AND CONFORMATIONAL-ANALYSES

We have developed an integrated approach for investigating the ''bioactive conformations'' of the main chain and side chains for the somatostatin analog c[Pro6-Phe7-D-Trp8-Lys9-Thr10-Phe11]. A series of analogs have been synthesized incorporating alpha-methylated and beta-methylated residues at positions 7, 8, and 11. These analogs display dramatic differences in in vitro binding affinities for somatostatin receptors. Using 500-MHz H-1 NMR and computer simulations, we have the effect of main chain and side chain chiral methylations on the overall structure. The analyses of the changes of side chain topologies and subsequent binding affinities in the beta-methylated analogs have provided definitive evidence about the ''bioactive conformation'' of the side chains of Phe7, Trp8, and Phe11. The analyses of the alpha-methylated analogs have defined a ''folded'' feature for the peptide backbone. From this study, we have proposed a binding ''pocket'' for somatostatin analogs which consists of the side chains of Trp8 and Lys9, the peptide backbone, and the side chain of Phe11 in a ''folded'' topochemical array. In this ''folded'' conformation, the Trp8 side chain assumes the trans rotamer, while the Lys9 side chain assumes the gauche-rotamer, thus allowing a close proximity between these two side chains. The Phe11 side chain assumes the trans rotamer. The peptide backbone adopts a beta II' turn about Trp8-Lys9 and a beta VI turn about Phe11-Pro6. The overall structure is folded about Phe7 and Thr10 residues assuming a C-7 conformation for their phi and psi torsions. This model should have important implications on the future design of peptide or nonpeptide ligands with somatostatin-like activities.