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Conformational analysis of three NK1 tripeptide antagonists: a proton nuclear magnetic resonance study.

Abstract：

:Two new peptides, tailored after Ac-Thr-D-Trp(CHO)-Phe-NMeBzl (TRI), namely, Ac-Thr-D-Trp(CHO)-Phe-NMe alpha MeBzl (TRA) and Ac-Thr-D-Trp(CHO)-Oic-NMeBzl (TOI), in which Phe is replaced by (3aS, 7aS)-octahydroindole-2-carboxylic acid, proved more potent and selective NK1 antagonists. The conformational properties of all three compounds were investigated in solution by NMR spectroscopy and those of TRI analyzed in greater detail by means of systematic computer-assisted modeling. All conformers whose energy differs by less than 9 kcal/mol from the absolute minimum are different from the conformer proposed in a previous molecular modeling study by the discovers of TRI. Parallel calculations for TRA and TOI yield low-energy conformers similar to those of TRI but in a slightly different order. Comparison of the shapes of low-energy conformers of all three peptides with those of four typical rigid NK1 antagonists shows that putative bioactive conformations are indeed present in solution.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Caliendo G,Grieco P,Perissutti E,Santagada V,Saviano G,Tancredi T,Temussi PA

doi

10.1021/jm960213s

subject

Has Abstract

pub_date

1997-02-14 00:00:00

pages

594-601

issue

4

eissn

0022-2623

issn

1520-4804

pii

jm960213s

journal_volume

40

pub_type

杂志文章

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