Abstract: | Abstract: Dermorphin and Lys7]dermorphin, selective µ‐opioid receptor ligands originating from amphibian skin, have been modified with various electrophiles in either the ‘message’ or ‘address’ sequences as potential peptide‐based affinity labels for µ‐receptors. Introduction of the electrophilic isothiocyanate and bromoacetamide groups on the para position of Phe3 and Phe5 was accomplished by incorporating Fmoc‐Phe(p‐NHAlloc) into the peptide followed by selective deprotection and modification. The corresponding amine‐containing peptides were also prepared. The pure peptides were evaluated in radioligand binding experiments using Chinese hamster ovary (CHO) cells expressing µ‐ and δ‐opioid receptors. In dermorphin, introduction of the electrophilic groups in the ‘message’ domain lowered the binding affinity by > 1000‐fold; only Phe(p‐NH2)3]dermorphin retained nanomolar affinity for µ‐receptors. Modifications in the ‘address’ region of both dermorphin and Lys7]dermorphin were relatively well tolerated. In particular, Phe(p‐NH2)5,Lys7]dermorphin showed similar affinity to dermorphin, with almost 2‐fold higher selectivity for µ‐receptors. Phe(p‐NHCOCH2Br)5]‐ and Phe(p‐NHCOCH2Br)5,Lys7]dermorphin exhibited relatively high affinity (IC50 = 27.7 and 15.1 nm , respectively) for µ‐receptors. However, neither of these peptides inhibited 3H]DAMGO binding in a wash‐resistant manner. |