Journal of Medicinal Chemistry
Cite this: J. Med. Chem. 2009, 52, 7
Published March 16, 2009
research-article
Copyright © 2009 American Chemical Society
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Neurotensin(8−13) and two related analogues were used as model systems to directly compare various N-terminal peptide modifications representing both commonly used and novel capping groups. Each N-terminal modification prevented aminopeptidase cleavage but surprisingly differed in its ability to inhibit cleavage at other sites, a phenomenon attributed to long-range conformational effects. None of the capping groups were inherently detrimental to human neurotensin receptor 1 (hNTR1) binding affinity or receptor agonism. Although the most stable peptides exhibited the lowest binding affinities and were the least potent receptor agonists, they produced the largest in vivo effects. Of the parameters studied only stability significantly correlated with in vivo efficacy, demonstrating that a reduction in binding affinity at NTR1 can be countered by increased in vivo stability.
ACS Publications
General experimental procedures; synthesis schemes 1−4; serum degradation standard curves; analytical data and experimental procedures for compounds 19, 22, 25, and 28; analytical HPLC analysis and MALDI-TOF data for each of the target peptides. This material is available free of charge via the Internet.
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This article is cited by 34 publications.
