Structural Studies of Position 2 Modified Endomorphin-2 Analogs by NMR Spectroscopy and Molecular Modeling

• Autorzy: Janecka A. , Perlikowska R. , Gach K. , Fichna J. , Mazur A. , Kruszyński R. , Janecki T. , Jankowski S.
• Języki publikacji: EN

Abstrakty

EN

Endomorphin-2 (EM-2, Tyr-Pro-Phe-Phe-NH2) is an endogenous ligand for the mi-opioid receptor. To examine the importance of Pro2 in EM-2 structure, we synthesized a series of analogs in corporating piperidine-2-, 3- and 4-carboxylic acids (Pip, Nip and Inp, respectively) in position 2. Pip, Nip and Inp are six-membered mimics of Pro and can be considered as alfa-, beta- and gamma-amino acids, respectively. Receptor binding studies revealed that [(R)-Nip2]EM-2 had greatly in creased mi-opioid receptor affinity compared with the parent peptide, while two other analogs were in active. In order to determine which structural elements of [(R)-Nip2]EM-2 could be responsible for the out standing affinity of this analog, the solution conformations of EM-2 analogs in corporating Promimics were investigated by the combination of 2D 1H NMR measurements and molecular modeling calculations. Evaluating the ratios of cis/trans rotamers, aromatic inter actions and dihedral angles we have found that all three analogs exist as a mixture of cis/trans rotamers of the Tyr–Xaa peptide bond and have flexible, extended conformations, with no intramolecular hydrogen bonds or aromatic ring inter actions observed for EM-2. The obtained results do not allow to draw conclusions on the bioactive conformation of the most active analog. We can suggest that a well known preference of the substituents to occupy equatorial positions in six-membered rings, to gether with a greater distance between Tyr1 and Phe3 aromatic rings, in Nip, which is a beta-amino acid, as compared with EM-2, are the main differentiating factors which are responsible for the exceptional affinity of [(R)-Nip2]EM-2.

Słowa kluczowe

EN

opioid agonist; endomorphin analogs; bioactive conformation; isomerization; unnatural amino acids

• Wydawca: Polskie Towarzystwo Chemiczne
• Czasopismo: Polish Journal of Chemistry
• Rocznik: 2009
• Tom: Vol. 83, nr 7
• Strony: 1293--1307
• Opis fizyczny: Bibliogr. 33 poz., rys.

Twórcy

autor

Janecka A.

autor

Perlikowska R.

autor

Gach K.

autor

Fichna J.

autor

Mazur A.

autor

Kruszyński R.

autor

Janecki T.

autor

Jankowski S.

• Laboratory of Biomolecular Chemistry, Medical University of Łódź, Mazowiecka 6/8, 92-215 Łódź, Poland phone: [phone]; fax: [phone],

Bibliografia

• 1.            Zadina J.E., Hackler L., Ge J.-L. and Kastin A.J., Nature, 386, 499 (1997).
• 2.            Horvath G., Szikszay M., Tömböly C. and Benedek G., Life Sei., 65, 2635 (1999).
• 3.            Obara I., Przewlocki R. and PrzewlockaB., Neurosci. Lett., 360, 85 (2004).
• 4.            Przewlocka B., Mika J., Labuz D., Toth G. and Przewlocki R., Eur. J. Pharmacol, 367, 189 (1999).
• 5.            Czapla M.A., Gozal D., Alea O.A., Beckerman R.C. and Zadina J.E., Am. J. Respir. Crit. Care Med., 162, 994 (2000).
• 6.            Yamazaki T., Ro S., Goodman M., Chung N.N. and Schiller P.W., J. Med. Chem., 36, 708 (1993).
• 7.            Paterlini M.G., Avitabile F., Ostrowski B.G., Ferguson D.M. and Portoghese P.S., BiophysJ., 78, 590 (2000).
• 8.            Podlogar B.L., Paterlini M.G., Ferguson D.M., Leo G.C., Demeter DA., Brown F.K. and Reitz A.B., FEBSLett., 439, 13 (1998).
• 9.            Fiori S., Renner C, Cramer J., Pegoraro S. and Moroder L., J. Mol. Biol., 291 163 (1999).
• 10.          In Y, Minoura K., Ohishi H., Minakata H., Kamigauchi M., Sugiura M. and Ishida T. J. Pept. Res., 58, 399 (2001).
• 11.          Leitgeb B., Szekeres A., Manczinger L., Vägvölgyi C. and Kredics L., Chem. Biodivers., 4,1027 (2007).
• 12.          Leitgeb B., Szekeres A. and Toth G., J. Pept. Res., 62, 145 (2003).
• 13.          Leitgeb B., Otvös F. and Töth G., Biopolymers, 68,497 (2003).
• 14.          Eguchi M., Shen RY, Shea J.P., Lee M.S. and Kahn M., J. Med. Chem., 45, 1395 (2002).
• 15.          Shao X., Gao Y, Zhu C, Liu X., Yao J., Cui Y and Wang R, Bioorg. Med. Chem., 15, 3539 (2007).
• 16.          Okada Y, Fujita Y, MotoyamaT., Tsuda Y, Yokoi T, Li T., Sasaki Y, Ambo A., Jinsmaa Y, Bryant S.D. and Lazarus L.H., Bioorg. Med. Chem., 11, 1983 (2003).
• 17.          Doi M., Asano A., Komura E. and Ueda Y, Biochem. Biophys. Res. Commun., 297, 138 (2002).
• 18.          Toth G., Keresztes A., Tomboly C, Peter A., Fulop F., Tourwe D., Navratilowa E., Varga E., Roeske W.R, Yamamura H.I., Szucs M. and Borsodi A., Pure Appl. Chem., 76, 951 (2004).
• 19.          Keresztes A., Szucs M., Borics A., Köver K.E., Forrö E, Fülöp F., Tomboly C, P&er A., Pähi A., Fabian G., Muränyi M. and Töth G., J. Med. Chem., 51, 4270 (2008).
• 20.          Keller M., Boissard C, Patiny L., ChungN.N., Lemieux C, Mutter M. and Schiller PW, J. Med. Chem., 44,3896 (2001).
• 21.          Staniszewska R., Fichna J., Gach K, Toth G., Poels J., Vanden Broeck J. and Janecka A., Chem. Biol. Drug. Das., 72, 91 (2008).
• 22.          TopSpin (version 2.1, Bruker BioSpin GmbH).
• 23.          Keller R.L.J., The Computer Aided Resonance Assignment Tutorial, Cantina Verlag, Goldau, CH (2004).
• 24.          Trzesniak D., Glattli A., Jaun B. and van Gunsteren W.F., J. Am. Chem. Soc., 127,14320 (2005).
• 25.          Lindahl E., Hess BA. and van der Spoel D., J. Mol. Mod., 7, 306 (2001).
• 26.          van der Spoel D., Lindahl E., Hess B., Groenhof G., Mark A.E. and Berendsen H.J.C., J. Comput. Chem., 26, 1701 (2005).
• 27.          Berendsen H.J.C., Postma J.P.M., DiNola A. and Haak J.R., J. Chem. Phys., 81, 3684 (1984).
• 28.          EssmannU.,PereraL.,BerkowitzM.L.,DardenT,LeeH.andPedersenL.G., J. Chem. Phys., 103,8577 (1995).
• 29.          Ryckaert J.P., Ciccotti G. and Berendsen H.J.C., J. Comput. Phys., 23, 327 (1977).
• 30.          Kessler H., Angew. Chem. Int. Ed. Engl., 21, 512 (1982).
• 31.          Zimmerman S.S., Pottle M.S., Nemethy G. and Scheraga H.A., Macromolecules, 10, 1 (1977).
• 32.          Leitgeb B. and Töth G., Eur. J. Med. Chem., 40, 674 (2005).
• 33.          Brandl M., Weiss M.S., Jabs A., Suhnel J. and Hilgenfeld R., J. Mol. Biol, 307, 357 (2001).