title: Mimicking of Arginine by Functionalized N(ω)-Carbamoylated Arginine As a New Broadly Applicable Approach to Labeled Bioactive Peptides: High Affinity Angiotensin, Neuropeptide Y, Neuropeptide FF, and Neurotensin Receptor Ligands As Examples.
abstract: Derivatization of biologically active peptides by conjugation with fluorophores or radionuclide-bearing moieties is an effective and commonly used approach to prepare molecular tools and diagnostic agents. Whereas lysine, cysteine, and N-terminal amino acids have been mostly used for peptide conjugation, we describe a new, widely applicable approach to peptide conjugation based on the nonclassical bioisosteric replacement of the guanidine group in arginine by a functionalized carbamoylguanidine moiety. Four arginine-containing peptide receptor ligands (angiotensin II, neurotensin(8-13), an analogue of the C-terminal pentapeptide of neuropeptide Y, and a neuropeptide FF analogue) were subject of this proof-of-concept study. The N(ω)-carbamoylated arginines, bearing spacers with a terminal amino group, were incorporated into the peptides by standard Fmoc solid phase peptide synthesis. The synthesized chemically stable peptide derivatives showed high receptor affinities with Ki values in the low nanomolar range, even when bulky fluorophores had been attached. Two new tritiated tracers for angiotensin and neurotensin receptors are described.
authors.affiliation: Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg , Universitätsstrasse 31, D-93053 Regensburg, Germany.
authors.forename: Max
authors.initials: M
authors.lastname: Keller
authors.affiliation: Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg , Universitätsstrasse 31, D-93053 Regensburg, Germany.
authors.forename: Kilian K
authors.initials: KK
authors.lastname: Kuhn
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University , Schuhstrasse 19, D-91052 Erlangen, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Einsiedel
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University , Schuhstrasse 19, D-91052 Erlangen, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.affiliation: Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg , Universitätsstrasse 31, D-93053 Regensburg, Germany.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Biselli
authors.affiliation: Institut de Pharmacologie et Biologie Structurale, CNRS/IPBS , 205 route de Narbonne, 31077 Toulouse cedex 5, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Mollereau
authors.affiliation: Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg , Universitätsstrasse 31, D-93053 Regensburg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Wifling
authors.affiliation: Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg , Universitätsstrasse 31, D-93053 Regensburg, Germany.
authors.forename: Jaroslava
authors.initials: J
authors.lastname: Svobodová
authors.affiliation: Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg , Universitätsstrasse 31, D-93053 Regensburg, Germany.
authors.forename: Günther
authors.initials: G
authors.lastname: Bernhardt
authors.affiliation: Department of Molecular Biology, University of Salzburg , Billrothstrasse 11, A-5020 Salzburg, Austria.
authors.forename: Chiara
authors.initials: C
authors.lastname: Cabrele
authors.affiliation: Faculty of Sciences and Bioengineering Sciences, Vrije Universiteit Brussel , Pleinlaan 2, B-1050 Brussels, Belgium.
authors.forename: Patrick M L
authors.initials: PM
authors.lastname: Vanderheyden
authors.affiliation: Department of Chemistry and Pharmacy, Emil Fischer Center, Friedrich Alexander University , Schuhstrasse 19, D-91052 Erlangen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
authors.affiliation: Institute of Pharmacy, Faculty of Chemistry and Pharmacy, University of Regensburg , Universitätsstrasse 31, D-93053 Regensburg, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Buschauer
mesh_terms: D000804:Angiotensin II / Q000737:chemistry / Q000494:pharmacology*; D001120:Arginine / Q000031:analogs & derivatives* / Q000737:chemistry; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D009478:Neuropeptide Y / Q000737:chemistry / Q000494:pharmacology*; D009496:Neurotensin / Q000737:chemistry / Q000494:pharmacology*; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010446:Peptide Fragments / Q000737:chemistry / Q000494:pharmacology*; D011945:Receptors, Angiotensin / Q000378:metabolism*; D018013:Receptors, Neuropeptide / Q000819:agonists / Q000378:metabolism*; D018028:Receptors, Neurotensin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D009478:Neuropeptide Y; D009842:Oligopeptides; D010446:Peptide Fragments; D011945:Receptors, Angiotensin; D018013:Receptors, Neuropeptide; D018028:Receptors, Neurotensin; D000804:Angiotensin II; D009496:Neurotensin; C054381:neurotensin (8-13); D001120:Arginine; C053651:phenylalanyl-leucyl-phenylalanyl-glutaminyl-prolyl-glutaminyl-arginyl-phenylalaninamide