Prerequisite for His4 in deltorphin A for highδ opioid receptor selectivity

Analysis of deltorphin A position 4 analogues included: backbone constrained NαMeHis, spinacine (Spi), NαMePhe and the tetrahydroisoquinoline-3-carboxylic acid (Tic); spatially confined side-chain (Phg); and imidazole alkylation ofL- andD-His4 enantiomers. Highδ selectivity was lost with the following replacements: NαMeHis4, NαMePhe4 and Phg4 reducedδ binding and the constrained residues also increasedµ binding; ring closure between the side-chain and amino group to yield Spi4 or Tic4 increasedµ affinity. Imidazole methylation of His4 marginally affected opioid binding and doubledδ selectivity; alkylatedD-His4-derivatives generally maintainedδ selectivity in spite of decreasedδ affinities. Thus, His4 imidazole preservesδ selectivity by facilitating highδ binding and by repulsion at theµ receptor. Several low energy conformers of deltorphin A indicated that the His4 imidazole preferred a spatial orientation parallel to the phenolic side-chain of Tyr1 suggestive that this conformation might contribute to highδ affinity and selectivity.