of Work: Structure-activity studies on d-opioid heptapeptide agonists and selective d-opioid di- and tripeptide antagonists containing Dmt-Tic were modified to enhance membrane permeability. Introduction of Aib in agonists amplified activities and amphiphilicity due to a-helical formation. The antagonists were modified at N- and C-termini with hydrophobic constituents that increased biological stability by eliminating cyclization to a diketopiperazines, nonetheless cyclo(Dmt-Tic) exhibited a unique conformation whose activity was less than linear molecules. N-Alkylation with methyl groups retained high d affinity and selectivity, whereas ethyl, piperidine, pyrrolidine, or pyyrole reduced affinity to the 1-2 nM range and subsequently decreased selectivity. C-Terminal modification (methoxy, hydrazide, methyl amide, adamantanyl amide) reduced d-selectivity by enhancing m-affinity, such that adamantanyl amide resulted in a peptide with high affinity for d- and m-receptors and agonist bioactivities. A complementary system that induces pain (nociception) through a heptadecapeptide represents the natural regulatory system on opioid effects. Structure-activity relationships revealed that nociceptin (1-13) is the minimal bioactive compound and various substitutions affected receptor and bioactivities. Thus, a combination of unique opioid agonists and antagonists, and the heptadecapeptide of the nociceptin system would permit us to better understand treatment of pain and differentiate opioid from antiopioid functions in clinical situations.
