Extended TIP(P) analogues as precursors for labeled delta-opioid receptor ligands

Tyr-Tic-Phe-Phe-OH (TIPP) and the shorter Tyr-Tic-Phe-OH (TIP) peptides are potent and highly selective antagonists at the delta-opioid receptor and, therefore, are ideal candidates for the attachment of labels to assist in the study of delta-opioid receptors. Peptides extended at the C-terminus with residues which can be used as handles for further modification and/or labeling (i.e. Asx, Glx, and Lys) were synthesized. The TIPP-D/L-Asx/Glx derivatives exhibited similar delta-receptor affinity to TIPP (K(i) = 5-10 nM vs K(i) = 6 nM), and neither the location of the carboxylic acid moiety nor the stereochemistry of the C-terminal residue significantly affected the delta-receptor affinity of these derivatives. Extension of TIPP with an additional residue did not increase mu-receptor affinity, even though the position of the acidic group, which imparts delta-receptor selectivity to TIPP, was shifted relative to the carboxylic acid moiety of TIPP. The delta-receptor affinities of the TIP-D/L-Asx/Glx derivatives were found to be influenced mainly by the position of the carboxylic acid function rather than the stereochemistry of the C-terminal residue. TIP(P)-D/L-Lys(Ac)-OH derivatives exhibited moderate delta-receptor affinity (K(i)(delta) = 16-28 nM). The most potent compounds found in the extended TIP(P) series were TIPP-D-Gln-OH and TIP-D-Gln-OH (K(i)(delta) = 5 nM) which had similar affinities to TIPP.