| Autor: |
Low, C. M. R., Black, J. W., Broughton, H. B., Buck, I. M., Davies, J. M. R., Dunstone, D. J., Hull, R. A. D., Kalindjian, S. B., McDonald, I. M., Pether, M. J., Shankley, N. P., Steel, K. I. M. |
| Zdroj: |
Journal of Medicinal Chemistry; September 21, 2000, Vol. 43 Issue: 19 p3505-3517, 13p |
| Abstrakt: |
The two hormones cholecystokinin and gastrin share the same C-terminal sequence of amino acids, namely Gly29-Trp30-Met31-Asp32-Phe33-NH2. Nevertheless, this congruence has not precluded using this structure to develop selective ligands for either CCK1 or CCK2 receptors. Manipulation of the hydrophobic residues at positions 31 and 33 gave a series of CCK1 tripeptide antagonists, typified by N-t-BOC-Trp-2-Nal-Asp-2-(phenyl)ethylamide (pKB 6.8 ± 0.3). Molecular modeling was used to identify the bioactive conformation of these CCK1-selective compounds and prompted the design of new peptoid structures. We aimed to maintain the conformation of the parent series by exploiting patterns of hydrogen-bonding and π-stacking interactions present in the original molecule, rather than introducing additional covalent bonds. The prototype, N-(succinyl-d-Asp-2-phenylethylamido)-l-Trp-2-(2-naphthyl)ethylamide, was a potent and selective CCK1 antagonist (pKB 7.2 ± 0.3). Furthermore, the new series showed patterns of biological activity that mirrored those of the parent tripeptides. These compounds contain elements of both peptide primary and secondary structure and represent a novel approach to designing peptidomimetics. Interesting results were obtained from comparing models of a representative tripeptide CCK1 antagonist with a conformation of CCK30-33 that others have proposed to be responsible for its activity at the CCK2 receptor. The results suggest that CCK1 and CCK2 receptors recognize enatiomeric dispositions of the Trp30 indole, Asp32 carboxylic acid, and C-terminal phenyl groups arrayed about a common backbone configuration. This functional chirality may underpin the mechanism by which these closely related receptor systems bind CCK30-33 and explain patterns of selectivity observed with optical isomers of a number of peptoid and nonpeptide ligands. |
| Databáze: |
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