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Opioid peptide analogs consisting entirely of aromatic amino acid residues and containing conformationally restricted phenylalanine derivatives in position 2 of the peptide sequence were synthesized and pharmacologically characterized in vitro. Both diastereoisomers of H-Tyr-(D or L)-NMePhe-Phe-Phe-NH2 (NMePhe is N alpha-methylphenylalanine) were mu-receptor-selective, were full agonists in the mu-receptor-representative guinea pig ileum assay, and were partial agonists in the mouse vas deferens assay, with the L-NMePhe2 analog displaying somewhat higher intrinsic activity than the D-NMePhe2 analog. Further conformational restriction at position 2 in the sequence, as achieved through substitution of D- or L-tetrahydro-3-isoquinoline carboxylic acid (Tic), produced a configuration-dependent differential effect on receptor selectivity and intrinsic activity, leading to a potent mu-selective mu agonist (the D-Tic2 analog) with increased intrinsic activity in the mouse vas deferens assay and to a potent delta-selective delta antagonist (the L-Tic2 analog). These results demonstrate that imposition of conformational constraints in a peptide not only may alter receptor selectivity but also may decrease, totally abolish, or even enhance intrinsic activity. The tetrapeptide H-Tyr-Tic-Phe-Phe-NH2 was a moderately potent full agonist in the guinea pig ileum assay and, thus, represents a compound with mixed mu-agonist/delta-antagonist properties. The corresponding peptide with a free C-terminal carboxyl group H-Tyr-Tic-Phe-Phe-OH showed high delta-receptor affinity (Ki delta = 1.2 nM), unprecedented delta selectivity (Ki mu/Ki delta = 1410), high potency as delta antagonist (Ke = 3-8 nM against various delta agonists in the mouse vas deferens assay) and, unlike other delta antagonists, had no mu-antagonist properties. The tripeptides H-Tyr-Tic-Phe-OH and H-Tyr-Tic-Phe-NH2 were also delta antagonists.

proceedings of the national academy of sciences of the united states of america

Differential stereochemical requirements of mu vs. delta opioid receptors for ligand binding and signal transduction: development of a class of potent and highly delta-selective peptide antagonists.