Hybrid analogues of the µ opioid agonists endomorphin and [Dmt ]DALDA (H-Dmt-D-Arg-Phe-Lys-NH , Dmt = 2',6'-dimethyltyrosine) containing cis-4-amino-Pro, trans-4-amino-Pro, cis-4-aminoethyl-Pro or cis-4-guanidinylethyl-Pro in the 2 position of the peptide sequence were synthesized. None of the compounds retained high µ opioid agonist activity and, unexpectedly, substitution of cis-4-amino-Pro resulted in a novel class of potent µ opioid antagonists. In particular, the compound H-Dmt-cis-4-amino-Pro-Trp-Lys-NH (CZ-1) turned out to be a highly selective µ opioid antagonist with ~1 nM µ receptor binding affinity.
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