2758
G. Cardillo et al. / Bioorg. Med. Chem. Lett. 10 (2000) 2755±2758
On the other hand, it is possible that the substitution of
Pro with b-(R)-Pro gives a tetrapeptide with a more
appropriate conformation to bind to m-opioid receptors
than endomorphin-1. This hypothesis is in agreement
with the observation that Tyr, Trp, and Phe seem to be
important to determine hydrogen bonds and hydro-
phobic interactions with the receptor, while proline
seems to be a spacer that induces the other residues to
assume the proper spatial orientation for the ligand±
receptor complex formation.5a,8,20 Although it is possi-
ble that endomorphin-1 (13) and Tyr-b-(R)-Pro-Trp-
PheNH2 (19) interact with the receptor in distinct ways,
it is also possible that they ®t the same site, owing to the
tetrapeptide chain ¯exibility. Moreover, it has been
pointed out that a certain degree of ¯exibility should
also be considered for the receptor conformation,
allowing molecules with dierent shapes to bind to the
same part of a receptor (`induced ®t').21
1998, 346, 111. (e) Sim, L. J.; Liu, Q.; Childers, R. S.; Selley,
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1165 and references therein.
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Acknowledgements
13. (a) Borman, S. C&EN 1997, 32. (b) Seebach, D.; Abele, S.;
Gademann, D.; Guichard, G.; Hintermann, T.; Jaun, B.;
Mattews, J. L.; Schreiber, J. V.; Oberer, L.; Hommel, U.;
Widmer, H. Helv. Chim. Acta 1998, 81, 932 and references
therein. (c) Appella, D. H.; Barchi, J. J., Jr.; Durell, S. R.;
Gellman, S. H. J. Am. Chem. Soc. 1999, 121, 2309 and refer-
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We thank M.U.R.S.T. Co®n and Bologna University
for ®nancial support of this research. We are also
thankful to Recordati S.p.a. for penicillin G acylase
supported on Eupergit.
References and Notes
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