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-C beta and C beta-C 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 delta-receptor over the mu-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 delta-receptor.