Structural requirements for binding to the δ opioid receptor: Alkyl replacements at the third residue of deltorphin I

Summary

The naturally occurring heptapeptide deltorphin I (Tyr-d-Ala-Phe-Asp-Val-Val-Gly-NH₂) exhibits extremely high affinity and selectivity for the δ opioid receptor. In an ongoing investigation of the features of this compound that confer these properties, seven new analogs of the peptide, in which phenylalanine at position three was replaced with amino acids containing alkyl side chains, were synthesized and tested for binding to μ, δ, and κ opioid receptors. These substitutions, including tert-leucine, tert-butylalanine, α-aminobutyric acid, norvaline, norleucine, β-cyclopentylalanine and octahydroindole-2-carboxylic acid, assessed the importance of aromaticity and lipophilicity/steric distribution of the side chain at this position in the binding interaction. Findings indicated that: (i) aromaticity at position three is not required for binding, and (ii) hydrophobic character, size, steric distribution and conformational flexibility influence affinity at the δ receptor. The data suggest that substitutions at the β-carbon of this residue disrupt the binding conformation of the peptide and possibly provide adverse steric effects.