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J Med Chem. 2003 Sep 11;46(19):4141-8.

In vitro analysis of stable, receptor-selective neurotensin[8-13] analogues.

Author information

1
Department of Pharmaceutical Sciences, Medical University of South Carolina, 280 Calhoun Street, P.O. Box 250140, Charleston, South Carolina 29425-2303, USA.

Abstract

A set of neurotensin[8-13] (NT[8-13]) analogues featuring substitution of non-natural cationic amino acids in the Arg(8) position have been synthesized and tested for binding potencies against the three cloned human NT receptors (hNTR-1, hNTR-2, hNTR-3), functional agonism of the hNTR1 and for rat serum stability. Three distinct classes of peptides have been identified: Class 1 features alkyl-Arg analogues at Arg(8), Class 2 features alpha-azido-cationic amino acids at Arg(8), and Class 3 feature modified Arg(8) and Tyr(11) residues. Most of the peptides maintain or exceed the binding potency of NT[8-13] to hNTR-1. Class 2 analogues exceed the binding potency of NT[8-13] to hNTR-2 with KK19 binding with higher affinity to hNTR-2 than hNTR-1. Peptides with enhanced binding potencies for hNTR-3 were not found. All analogues are functional agonists of the hNTR1 receptor as indicated by phosphoinositide (PI) determination. Serum stability increased with peptide classification where the half-life of Class 1 < Class 2 < Class 3 which are stable to rat serum for > 24 h.

PMID:
12954066
DOI:
10.1021/jm0300633
[Indexed for MEDLINE]

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