title: Comparison of N-terminal modifications on neurotensin(8-13) analogues correlates peptide stability but not binding affinity with in vivo efficacy.
abstract: 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.
authors.affiliation: Department of Pharmaceutical Sciences, Medical University of South Carolina, Charleston, South Carolina 29425, USA.
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Orwig
authors.forename: McKensie R
authors.initials: MR
authors.lastname: Lassetter
authors.forename: M Kyle
authors.initials: MK
authors.lastname: Hadden
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Dix
mesh_terms: D000626:Aminopeptidases / Q000097:blood; D000818:Animals; D001667:Binding, Competitive; D001831:Body Temperature / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D006801:Humans; D066298:In Vitro Techniques; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D009496:Neurotensin / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010446:Peptide Fragments / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018028:Receptors, Neurotensin / Q000819:agonists / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D010446:Peptide Fragments; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; D009496:Neurotensin; C054381:neurotensin (8-13); D000626:Aminopeptidases; D002118:Calcium