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 w ith residues which can be used as handles for further modification and/or l abeling (i.e. Asx, Glx, and Lys) were synthesized. The TIPP-D/L-Asx/Glx der ivatives 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 de lta -receptor affinity of these derivatives. Extension of TIPP with an addi tional residue did not increase Ct-receptor affinity, even though the posit ion of the; acidic group, which imparts delta -receptor selectivity to TIPP , was shifted relative to the carboxylic acid moiety of TIPP. The delta -re ceptor affinities of the TIP-D/L-Asx/Glx derivatives were found to be influ enced mainly by the position of the carboxylic acid function rather than th e stereochemistry of the C-terminal residue.: TIP(P)-D/L-Lys(Ac)-OH derivat ives exhibited moderate delta -receptor affinity (K-i(delta) = 16-28 nM). T he most potent compounds found in the extended TIP(P) series were TIPP-D-Gl n-OH and TIP-D-Gln-OH (K-i(delta)= 5 nM) which had similar affinities to TI PP.