A topographical model of μ‐opioid and brain somatostatin receptor selective ligands NMR and molecular dynamics studies

We have refined the ¹H NMR‐based conformations of the μ‐opioid receptor selective peptides related to somatostatin of general formula Xxx‐Yyy¹‐Cys‐Zzz‐D‐Trp‐Lys(Orn)⁵‐Thr‐Peh‐Thr⁸‐NH₂, where Xxx, Yyy, Zzz are 0, d‐Phe and Tyr for 1; 0, d‐Tic and Tyr for 2; Gly, d‐Tic and Tyr for 3; and 0, d‐Phe and Tic for 4, respectively, (Kazmierski et al., J. Am. Chem. 113, 2275–2283), using a molecular‐dynamics approach. We present evidence that the NMR data are compatible with βII′‐, γ‐ and γ′‐turns for the central tetrapeptide Tyr‐D‐Trp‐Lys/Orn‐Thr. Based on detailed structural and topographical considerations, we suggest that the μ‐opioid receptor selectivity of 2 is due to a particular spatial arrangement of aromatic side chains of d‐Tic¹ and Tyr³ (7.5 Å), and that the opioid receptor recognition domain is located in the N‐terminal part of the peptide while the somatostatin receptor recognition domain is determined by the central, turn forming part of this class of cyclic peptides. A model for a μ‐opioid selective ligand has emerged from these studies that shows excellent structural similarities to rigid opioid alkaloids.