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Biophys J, February 2000, p. 590-599, Vol. 78, No. 2
*Department of Medicinal Chemistry and Supercomputer Institute and
Department of Biochemistry, Biophysics, and Molecular
Biology, University of Minnesota, Minneapolis, Minnesota 55455 USA
A series of diastereoisomers of endomorphin-1
(EM1,
Tyr1-Pro2-Trp3-Phe4-NH2)
have been synthesized and their potency measured using the guinea pig
ileum assay. [D-Phe4]EM1 possessed 1/10 the
potency of EM1, while potencies of
[D-Tyr1]EM1 and
[D-Trp3]EM1 were 50- and 100-fold lower,
respectively. Drastic loss of activity occurred in the
[D-Pro2]EM1 peptide. The structural
determinants for the inactivity and reduced potency of the
diastereoisomers were investigated using NMR spectroscopy and
conformational analysis. Simulations of
trans-[D-Pro2]EM1 using
NOE-derived distance constraints afforded well-defined structures in
which Tyr and Trp side chains stack against the proline ring. The
inactivity of [D-Pro2]EM1 was explained by
structural comparison with EM1 (Podlogar et al.,1998, FEBS
Lett. 439:13-20). The two peptides showed an opposite
orientation of the Trp3 residue with respect to
Tyr1, thus suggesting a role of Pro2 as a
stereochemical spacer in orienting Trp3 and
Phe4 toward regions suitable for µ-receptor interaction.
The agonist activity of [D-Tyr1]EM1 and
[D-Trp3]EM1 was attributed to their ability
to adopt low-energy conformations that mimic those of EM1. The
requirements for µ-receptor activation were examined further by
comparing EM1 with the µ-peptide [D-Ala2,
MePhe4, Gly-ol]-enkephalin (DAMGO). Conformations of DAMGO
with a Tyr1-MePhe4 phenyl ring separation of
~12 Å were found to mimic Tyr1-Phe4 of EM1,
thus suggesting overlapping binding modes between these two peptides.
Biophys J, February 2000, p. 590-599, Vol. 78, No. 2
© 2000 by the Biophysical Society 0006-3495/00/02/590/10 $2.00
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