Topochemical design of bioactive peptides and peptidomimetics.

For the studies of bioactive peptides, our laboratories have been employed an integrated approach including synthesis, bioassays, and conformational analysis. To obtain highly potent, selective and metabolically stable analogs, peptidomimetics such as peptide backbone modifications (retro-inverso structures), constrained amino acids, and cyclic structures have been incorporated into many bioactive peptide sequences. The conformational studies of the resulting analogs have led to topochemical models for the bioactivities of those peptides. This lecture will be focused on the results of such studies on opioids and somatostatin. We have synthesized numerous opioid analogs with various peptidomimetics based on three classes: enkephalins, dermorphin-deltorphins, and morphiceptins. Many of these analogs exhibit high potency, selectivity, and metabolic stability. Conformational studies of these analogs have enabled us to define the structural characteristics necessary for bioactivities of morphiceptins, dermorphins, enkephalins, and deltorphins. From these results, we can propose conformational models responsible for bioactivities at the mu- and delta-receptors. Our studies of cyclic somatostatin analogs are based on the highly active Merck analog c(-Pro6-Phe7-D-Trp8-Lys9-Thr10-Phe11-) (where the superscripts denote position in native somatostatin). To investigate the topochemical preference of backbone and side chains, unusual amino acids, including beta-methylphenylalanine7 or 11, beta-methyltryptophan8, as well as backbone modifications such as retro-inverso structures have been incorporated. The bioactivity profiles of these peptidomimetic molecules provide much information on the effects of backbone and side chain constraints on bioactivity.