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R. Millet et al
which alter rumen fermentation. Int. J. Peptide Protein Res. 16:
464–470
2a may have an important role in the interaction with
NK1 receptor when affinities of 2a and 1a are compared.
Another element in NK1 recognition was made apparent
by introducing building units such as spirolactam, lac-
tam or proline. These led to an increase in NK1 affinity
but not in NK2 affinity, unlike that which occurred with
Cbz-Gly-Leu-Trp-OBzl(CF3)2. The selectivity of 2a, 3
and 4 for NK1 receptors, when compared with that of
Cbz-Gly-Leu-Trp-OBzl(CF3)2, seems to be in relation
with the conformational restraints imposed by the geo-
metrical features of their N-terminal sequence. Com-
pounds 2a, 3 and 4 would gain in affinity for the NK1
receptor by virtue of greater entropy binding.
Freidinger, R. M., Perlow, D. S., Veber, D. F. (1982) Protected
lactam-bridged dipeptides for use as conformational constraint in
peptides. J. Org. Chem. 47: 104–109
Genin, M. J., Gleason, W. B., Johnson, R. L. (1993) Design, synthesis,
and X-ray crystallographic analysis of two novel spirolactam sys-
tems as β-turn mimics. J. Org. Chem. 58: 860–866
Hinds, M. G., Welsh, J. H., Brennand, D. M., Fisher, J., Glennie, M.
G., Richards, N. G. J., Turner, D. L., Robinson, J. A. (1991) Syn-
thesis, conformational properties, and antibody recognition of
peptides containing β-turn mimetics based on α-alkylproline de-
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Sramek, J. J., Reines, S. A., Liu, G., Snavely, D., Wyatt-Knowles,
E., Hale, J. J., Mills, S. G., MacLoss, M., Swain, C. J., Harrison,
T., Hill, R. G., Hefti, F., Scolnick, E. M., Cascieri, M. A., Chicchi,
G. G., Sadowski, S., Williams, A. R., Hewson, L., Smith, D.,
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stance P receptors. Science 281: 1640–1645
Conclusion
We have described the synthesis and structure–activity
relationships for a series of analogues of spirolactam
derivatives. In this case, our strategy consisted of syn-
thesizing new compounds based on the C-terminal se-
quence of GR71251. This approach showed that the
Trp-OBzl(CF3)2 moiety was essential for NK1 affinity
and that introducing building units leading to con-
strained peptides increased selectivity for NK1receptors.
Conformational analyses of 2a, 3 and 4 are ongoing.
These compounds constitute a useful starting point for
new substance P antagonists and represent attractive
leads for further studies on metabolically more stable
analogues.
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