Conformational analysis of μ‐selective [D‐Ala2,MePhe4]enkephalins

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Abstract
The conformational space of the potent μ‐selective opioids [D‐Ala2,MePhe4,Gly‐o15]enkephalin (DAGO) and [D‐Ala2,MePhe4,Gly‐o15]enkephalin (FK 33‐824) has been analyzed by 1H‐NMR spectroscopy and theoretical calculations involving systematic conformational searching and energy minimizations. A cis‐trans equilibrium of the Gly3‐MePhe4 amide bond is induced by the N‐methyl group, and the more energetically favoured trans isomer is proposed as the biologically relevant form. A compact interaction between the side chains of Tyr1 and D‐Ala2 was demonstrated by NOE and ROE effects in both peptides in D2O and DMSO‐d6, further supported by shielding of the D‐Ala2 methyl protons in both solvents. Analysis of coupling constants, NOE and ROE data indicated significant restriction of the conformational freedom of the MePhe4 side‐chain for both peptides in the two solvents. The NMR results and theoretical calculations point towards folded low energy conformations characterized by a β11‐type turn around Gly3‐MePhe4. For the trans isomer, a Tyr1‐MePhe4 phenyl ring separation between 8.5 and 12.5 Å was accompanied by proximity between the D‐Ala2 side chain and the C‐terminal in low energy conformations The results are in good agreement with available data on related active enkephalins. The conformational effects induced by simultaneous incorporation of D‐Ala2 and MePhe4 in enkephalins is discussed in the light of the enhanced μ‐opioid receptor selectivity and activity of these peptides.

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