title: In vitro analysis of stable, receptor-selective neurotensin[8-13] analogues.
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.
authors.affiliation: Department of Pharmaceutical Sciences, Medical University of South Carolina, 280 Calhoun Street, P.O. Box 250140, Charleston, South Carolina 29425-2303, USA.
authors.forename: Kyle P
authors.initials: KP
authors.lastname: Kokko
authors.forename: M Kyle
authors.initials: MK
authors.lastname: Hadden
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Orwig
authors.forename: Jean
authors.initials: J
authors.lastname: Mazella
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Dix
mesh_terms: D000595:Amino Acid Sequence; D000596:Amino Acids / Q000737:chemistry; D000818:Animals; D019556:COS Cells; D004355:Drug Stability; D006207:Half-Life; D006801:Humans; D009496:Neurotensin / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D010446:Peptide Fragments / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D010716:Phosphatidylinositols / Q000032:analysis / Q000096:biosynthesis; D051381:Rats; D018028:Receptors, Neurotensin / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization / Q000379:methods; D014162:Transfection
chemical_list: D000596:Amino Acids; D010446:Peptide Fragments; D010716:Phosphatidylinositols; D018028:Receptors, Neurotensin; D009496:Neurotensin; C054381:neurotensin (8-13)