Abstract
The neurotensin C-terminal hexapeptide, NT(8-13), which has been found to adopt a beta-strand-like conformation while bound to the NT1 receptor, was modified by the introduction of conformational constraints. Synthesis of the four stereoisomeric 4.4-spirolactams 1-4 and subsequent NT1 receptor binding studies showed that the restriction of psi(Pro10) to approximately 130 degrees leads to a more than 1000-fold increase of binding affinity for 1 (Ki = 12 nM) when compared to the more flexible analogue [NMeTyr11]NT(8-13).
MeSH terms
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Animals
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Binding, Competitive
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In Vitro Techniques
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Lactams / chemical synthesis*
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Lactams / chemistry
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Lactams / pharmacology
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Molecular Conformation
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Molecular Mimicry
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Neurotensin / chemistry*
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Neurotensin / pharmacology
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Oligopeptides / chemical synthesis*
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Oligopeptides / chemistry
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Oligopeptides / pharmacology
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Proline / chemistry*
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Protein Structure, Secondary
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Radioligand Assay
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Receptors, Neurotensin / drug effects
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Receptors, Neurotensin / metabolism
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Stereoisomerism
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Swine
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Tyrosine / chemistry
Substances
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Lactams
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Oligopeptides
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Receptors, Neurotensin
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neurotensin type 1 receptor
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Neurotensin
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Tyrosine
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Proline