.delta. Opioid receptor selectivity induced by conformational constraints in linear enkephalin-related peptides: proton 400-MHz NMR study and theoretical calculations

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Abstract
Introduction into the structure of the linear hexapeptide DSLET (Tyr-D-Ser-Gly-Phe-Leu-Thr) or DTLET (Tyr-D-Thr-Gly-Phe-Leu-Thr) of tert-butyl groups as constraints different from cyclization leads to a large increase in the selectivity for .delta. opioid binding site in the case of DSTBULET [Try-D-Ser-(OtBu)-Gly-Phe-Leu-Thr] (Ki.delta. = 6.14 nM; Ki.mu. = 374 nM) and BUBU [Tyr-D-Ser(OtBu)-Gly-Phe-Leu-Thr(OtBu)] (Ki.delta. = 4.68 nM; K1i.mu. = 475 nM) or a loss of affinity for DTTBULET [Tyr-D-Thr(OtBu)-Gly-Phe-Leu-Thr] (Ki.delta. = 866 nM; Ki.mu. = 4500 nM). This puzzling behavior is studied here by 400-MHz 1H NMR spectroscopy in DMSO-d6 solution and by theoretical calculations. When DSLET and DTLET are compared, the reduction in energetically accessible .vphi. and .psi. angles induced by the tert-butyl group in the D-Ser2 residue decreases the degree of freedom in the N-terminal part of the peptides. For DSTBULET and BUBU, the rigidification of the backbone evidenced by the appearance of the large NOE''s of Phe4 NH-Gly3 .alpha. and Gly3 NH-.alpha. and by the loss of the C7 folding around the D-Ser2 residue found in DSLET could explain the drastic loss of affinity for .mu. opioid receptors. In DTTBULET, a large change in the spatial orientation around the D-Thr2 (OtBu) residue forces the aromatic rings far from each other. Conformation analysis of these peptides by Metropolis calculations in agreement with NMR analysis suggesting that the preferential g- orientation of the Phe4 side chain, yielding a short distance (.ltoreq. 10 .ANG.) between the two aromatic rings, plays a crucial role in .delta. receptor selectivity. The most stable conformation of BUBU deduced from NMR is very similar to the conformation of .delta.-selective cyclo-[D-Pen2,L-Pen5]enkephalin and cyclo-[D-Pen2,D-Pen5]enkephalin, two severely constrained cyclic peptides. Moreover, the Tyr1 and Phe4 aromatic rings of BUBU can be easily superimposed on the corresponding rings in the rigid and selective .delta.-antagonist naltrindole.

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