Summary
In order to enforce different spatial orientations in the C-terminal hexapeptide of neurotensin (NT8−13) and to gain information about the importance of the 10–11 peptide bond for binding to NT receptors, the Pro10-Tyr11 fragment has been replaced with (2R,8S,8aR)-, (2S,8S,8aR)-, (2S,8S,8aS)-, (2S,8R,8aS)- and (2R,8R,8aS)-8-amino-2-benzyl-3-oxoindolizidine-2-carboxylic acid. Molecular dynamics calculations and energy minimization studies have shown that, contrarily to the Pro-Tyr moiety, none of these indolizidines display a tendency to adopt type I and III β-turns, but those having (8S,8aR) or (8R,8aS) stereochemistry essentially adopt extended conformations and the (8S,8aS) stereoisomer prefers a nonstandard folding. The four diastereomeric NT8−13 analogues incorporating (8S,8aR) or (8R,8aS) indolizidines displayed binding affinities for the brain NT receptor similar to that of [Ala11]-NT8−13 and only five- to ninefold lower than that of the corresponding analogue, [Phe11]NT8−13. Although this slight decrease could be attributed to differences in conformational behavior between these constrained NT8−13 analogues and [Phe11]NT8−13 or NT8−13, it is not clear whether the β-turn around Pro10-AA11 (AA=Phe, Tyr) is conserved upon receptor binding. An excessive restriction in the motions of the aromatic side chain, imposed by the highly steric constraint of the indolizidine moiety, emerges as an alternative explanation. The findings reported here demonstrate the possibility of replacing the Pro10-Tyr11 dipeptide in NT8−13 with a non-peptide residue without affecting considerably the affinity for brain NT receptors.
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García-López, M.T., Alkorta, I., Domínguez, M.J. et al. Constrained C-terminal hexapeptide neurotensin analogues containing a 3-oxoindolizidine skeleton. Lett Pept Sci 1, 269–276 (1995). https://doi.org/10.1007/BF00119767
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DOI: https://doi.org/10.1007/BF00119767