14‐Membered cyclic opioids related to dermorphin and their partially retro‐inverso modified analogues II. Preferred conformations in solution as studied by 1H‐NMR spectroscopy

Abstract

The ¹H-NMR studies were extensively carried out to elucidate preferred conformations of a series of 14-membered cyclic dermorphin analogues containing two phenylalanines at both the third and fourth positions, e.g., Tyr-c[D-A₂bu-Phe-Phe-(l and d)-Leu], Tyr-c[d-A₂bu-Phe-gPhe-(S and R)-mLeu], and Tyr-c[d-Glu-Phe-gPhe-(L and D)-rLeu]. The temperature coefficients of the amide proton chemical shifts, vicinal ¹H-¹H coupling constants for the NH-CH groupings, and nuclear Overhauser effects provided information regarding the preferred conformations of the backbones. The conformational preferences and flexibility of the side chains were also estimated from the vicinal ¹H-¹H coupling constants around the C-Cβ and C-Cβ bonds in the articulated side chains. A comparison of the results obtained was made with the results previously obtained for the corresponding enkephalin analogues containing a glycine at the third position. It was found that the replacement of the glycine with the phenylalanine at the third position increases the conformational flexibility of the molecules with an l-, or S-, residue at the fifth position but reduces the flexibility of the molecules with d-, or R-, residue at the same position. The rotating frame nuclear Overhauser experiments gave direct evidence for compact conformations, with the Tyr side chain folding back over the 14-membered ring in Tyr-c[d-Glu-Phe-gPhe-rLeu], which displays relatively high selectivity for the δ-receptor over the μ-receptor. This observation is in agreement with our model proposed for the cyclic enkephalin analogues: folded forms with close aromatic ring placement are required for the activity at the δ-receptor.