Delta opioid receptor selectivity induced by conformational constraints in linear enkephalin-related peptides: 1H 400-MHz NMR study and theoretical calculations.
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 [Tyr-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; Ki 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 phi 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Belleney
J
J
Département de Chimie Organique, U 266 INSERM, Paris, France.
Gacel
G
G
Fournié-Zaluski
M C
MC
Maigret
B
B
Roques
B P
BP
D000595:Amino Acid Sequence; D055598:Chemical Phenomena; D002621:Chemistry; D004121:Dimethyl Sulfoxide; D004743:Enkephalin, Leucine / Q000031:analogs & derivatives*; D004745:Enkephalins / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D011957:Receptors, Opioid / Q000378:metabolism*; D013696:Temperature
D004745:Enkephalins; D009842:Oligopeptides; D011957:Receptors, Opioid; C054868:tyrosyl-seryl(O-tert-butyl)-glycyl-phenylalanyl-leucyl-threonine; D004743:Enkephalin, Leucine; C034318:enkephalin, Ser(2), Leu(5), Thr(6)-; C037653:deltakephalin; D004121:Dimethyl Sulfoxide