Comparison of conformational properties of linear and cyclic δ selective opioid ligands DTLET (Tyr‐D‐Thr‐Gly‐Phe‐Leu‐Thr) and DPLPE (Tyr‐c[D‐Pen‐Gly‐Phe‐Pen]) by 1H n.m.r. spectroscopy

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Abstract
The preferential conformations of the δ selective opioid peptides DPLPE (Tyr‐c[D‐Pen‐Gly‐Phe‐Pen]) and DTLET (Tyr‐D‐Thr‐Gly‐Phe‐Leu‐Thr) were studied by 400 MHz 1H n.m.r. spectroscopy in DMSO‐d6 solution. In neutral conditions, the weak NH temperature coefficients of the C‐terminal residue (Pen5 or Thr6), associated with interproton NH‐NH and α‐NH NOE's (ROESY experiments), indicated large analogies between the backbone folding tendency of both the linear and cyclic peptides. Various γ and/or β turns may account for these experimental data. A similar orientation of the N‐terminal tyrosine related to the folded backbones is observed for the two agonists, with a probable γ turn around the amino acid in position 2. Finally, a short distance, about 10 Å, between Tyr and Phe side chains and identical structural roles for threonyl and penicillamino residues are proposed for both peptides. These results suggest the occurrence of similar conformers in solution for the constrained peptide DPLPE and the flexible hexapeptide DTLET. Therefore, it may be hypothesized that the enhanced δ selectivity of DPLPE is related to a very large conformational expense of energy needed to interact with the μ opioid receptor, a feature not encountered in the case of DTLET. These findings might allow peptides to be designed retaining a high affinity for δ opioid receptors associated with a very low cross‐reactivity with μ binding sites.

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