DE-NOVO DESIGN AND SYNTHESIS OF SOMATOSTATIN NONPEPTIDE PEPTIDOMIMETICS UTILIZING BETA-D-GLUCOSE AS A NOVEL SCAFFOLDING

Non-peptide peptidomimetics of the peptide hormone somatostatin (SRIF) were designed and synthesized, utilizing beta-D-glucose as a novel sc affolding. Such compounds resemble conventional peptide analogs in tha t they retain critical amino acid side chains but differ in that they are devoid of both the peptide backbone and amide surrogates. Structur e-activity relationships resulting from systematic deletion or modific ation of the side chains of 4a were consistent with expectations, with the exception that analogs 8a and gb, lacking an indole side chain, b ound to the SRIF receptor. A possible explanation for this unexpected result and its potential implications are discussed. Unexpectedly we a lso found that the primary amino group of Lys9 is not required for SRI F receptor binding or activation. Taken together, the results reported herein, and those described elsewhere, 1,2 support the validity of th e concept of non-peptide scaffolding and also demonstrate that non-pep tidal peptidomimetics can provide unexpected biological information no t previously available from natural ligands or their peptidal analogs.