Evaluation of lactam-bridged neurotensin analogues adjusting psi(Pro10) close to the experimentally derived bioactive conformation of NT(8-13).
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).
Department of Medicinal Chemistry, Emil Fischer Center, Friedrich Alexander University, Schuhstrasse 19, D-91052 Erlangen, Germany.
Holger
H
Bittermann
Jürgen
J
Einsiedel
Harald
H
Hübner
Peter
P
Gmeiner
D000818:Animals; D001667:Binding, Competitive; D066298:In Vitro Techniques; D007769:Lactams / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008968:Molecular Conformation; D018716:Molecular Mimicry; D009496:Neurotensin / Q000737:chemistry* / Q000494:pharmacology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011392:Proline / Q000737:chemistry*; D017433:Protein Structure, Secondary; D011869:Radioligand Assay; D018028:Receptors, Neurotensin / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism; D013552:Swine; D014443:Tyrosine / Q000737:chemistry
D007769:Lactams; D009842:Oligopeptides; D018028:Receptors, Neurotensin; C114036:neurotensin type 1 receptor; D009496:Neurotensin; D014443:Tyrosine; D011392:Proline