Newly Discovered Stereochemical Requirements in the Side-Chain Conformation of δ Opioid Agonists for Recognizing Opioid δ Receptors

Topographic design of peptide ligands using specialized topographically constrained amino acids can provide new insights into the stereochemical requirements for δ opioid receptors. A highly constrained tyrosine derivative, (2S,3S)-β-methyl-2′,6′-dimethyltyrosine [(2S,3S)-TMT], was prepared by asymmetric synthesis and incorporated in [D-Pen²,D-Pen⁵]enkephalin (δ₁) and Deltorphin I (δ₂). The results of binding assays and bioassays showed that the two analogues (3 and 4) acted very differently at δ opioid receptors. Further pharmacological evaluations suggested that they actually interact primarily with the δ₁ and δ₂ receptor subtypes, respectively. These results, and conformational studies using NMR and computer-assisted modeling, provided insights into the different stereochemical requirements opioid receptor and its subtypes.