Prerequisite for His(4) in deltorphin A for highδ opioid receptor selectivity.

Analysis of deltorphin A position 4 analogues included: backbone constrained N (α) MeHis, spinacine (Spi), N (α) MePhe and the tetrahydroisoquinoline-3-carboxylic acid (Tic); spatially confined side-chain (Phg); and imidazole alkylation ofL- andD-His(4) enantiomers. Highδ selectivity was lost with the following replacements: N (α) MeHis(4), N (α) MePhe(4) and Phg(4) reducedδ binding and the constrained residues also increasedµ binding; ring closure between the side-chain and amino group to yield Spi(4) or Tic(4) increasedµ affinity. Imidazole methylation of His(4) marginally affected opioid binding and doubledδ selectivity; alkylatedD-His(4)-derivatives generally maintainedδ selectivity in spite of decreasedδ affinities. Thus, His(4) imidazole preservesδ selectivity by facilitating highδ binding and by repulsion at theµ receptor. Several low energy conformers of deltorphin A indicated that the His(4) imidazole preferred a spatial orientation parallel to the phenolic side-chain of Tyr(1) suggestive that this conformation might contribute to highδ affinity and selectivity.