The opioid peptide TIPP (H-Tyr-Tic-Phe-Phe-OH, Tic:1,2,3,4-tetrahydroisoquinoline-3-car
boxylic acid) wassu
bstituted with Dmt (2',6'-dimethyltyrosine) and a new unnatural amino acid,
G SRC="/images/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-MeCha (
ges/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-methyl-cyclohexylalanine). This double substitution led to a new series of opioid peptides displaying subnanomolar
ges/gifchars/delta.gif" BORDER=0 > antagonist activity and
ges/entities/mgr.gif"> agonist or antagonist properties depending on the configuration of the
ges/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-MeCharesidue. The most promising analog, H-Dmt-Tic-(2S,3S)-
ges/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-MeCha-Phe-OH was a very selective
ges/gifchars/delta.gif" BORDER=0 > antagonistboth in the mouse vas deferens (MVD) assay (Ke = 0.241 ± 0.05 nM) and in radioligand binding assay (Ki
ges/gifchars/delta.gif" BORDER=0 >= 0.48 ± 0.05 nM, Ki
ges/entities/mgr.gif">/Ki
ges/gifchars/delta.gif" BORDER=0 > = 2800). The epimeric peptide H-Dmt-Tic-(2S,3R)-
ges/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-MeCha-Phe-OH and thecorresponding peptide amide turned out to be mixed partial
ges/entities/mgr.gif"> agonist/
ges/gifchars/delta.gif" BORDER=0 > antagonists in the guinea pig ileumand MVD assays. Our results constitute further examples of the influence of Dmt and
ges/gifchars/beta2.gif" BORDER=0 ALIGN="middle">-methyl substitutionas well as C-terminal amidation on the potency, selectivity, and signal transduction properties of TIPPrelated peptides. Some of these compounds represent valuable pharmacological tools for opioid research.