Document Detail

Design and structure-activity relationships of C-terminal cyclic neurotensin fragment analogues.
MedLine Citation:
PMID:  7830267     Owner:  NLM     Status:  MEDLINE    
Neurotensin (NT) is a linear tridecapeptide with a broad range of central and peripheral pharmacological effects. The C-terminal hexapeptide of NT (NT8-13) has been shown to possess similar properties to NT itself, and in fact, an analogue of NT8-13 (N alpha MeArg8-Lys-Pro-Trp-Tle-Leu13, Tle = tert-leucine) has been reported to possess central activity after peripheral administration. Cyclic derivatives of this hexapeptide were synthesized by a combination of solution and solid-phase peptide synthetic methodologies, and several analogues had low nanomolar binding affinity for the NT receptor. In particular, cyclo[Arg-Lys-Pro-Trp-Glu]-Leu (cyclized between the alpha amine of Arg and the gamma carboxylate of Glu) possessed 16 nM NT receptor affinity and was determined to be an agonist in vitro. 1H-NMR and 13C-edited 1H-NMR spectroscopy were performed on this and related cyclic analogues to help identify structural properties which may be important for receptor recognition. These cyclic peptides represent novel molecular probes to further investigate NT receptor pharmacology, as well as to advance our understanding of the structure-conformation relationships of NT and to help establish a working basis for additional pharmacophore mapping studies.
A M Sefler; J X He; T K Sawyer; K E Holub; D O Omecinsky; M D Reily; V Thanabal; H C Akunne; W L Cody
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Publication Detail:
Type:  Journal Article    
Journal Detail:
Title:  Journal of medicinal chemistry     Volume:  38     ISSN:  0022-2623     ISO Abbreviation:  J. Med. Chem.     Publication Date:  1995 Jan 
Date Detail:
Created Date:  1995-02-23     Completed Date:  1995-02-23     Revised Date:  2000-12-18    
Medline Journal Info:
Nlm Unique ID:  9716531     Medline TA:  J Med Chem     Country:  UNITED STATES    
Other Details:
Languages:  eng     Pagination:  249-57     Citation Subset:  IM    
Department of Chemistry, Parke-Davis Pharmaceutical Research, Division of the Warner-Lambert Company, Ann Arbor, Michigan 48106.
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MeSH Terms
Amino Acid Sequence
Calcium / metabolism
Cells, Cultured
Magnetic Resonance Spectroscopy
Molecular Sequence Data
Neurotensin / analogs & derivatives*,  chemistry,  metabolism
Peptide Fragments / chemistry
Peptides, Cyclic / chemistry*
Receptors, Neurotensin / metabolism*
Structure-Activity Relationship
Reg. No./Substance:
0/Peptide Fragments; 0/Peptides, Cyclic; 0/Receptors, Neurotensin; 39379-15-2/Neurotensin; 7440-70-2/Calcium

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