title: N(ω)-Carbamoylation of the Argininamide Moiety: An Avenue to Insurmountable NPY Y1 Receptor Antagonists and a Radiolabeled Selective High-Affinity Molecular Tool ([(3)H]UR-MK299) with Extended Residence Time.
abstract: Analogues of the argininamide-type NPY Y1 receptor (Y1R) antagonist BIBP3226, bearing carbamoyl moieties at the guanidine group, revealed subnanomolar Ki values and caused depression of the maximal response to NPY (calcium assay) by up to 90% in a concentration- and time-dependent manner, suggesting insurmountable antagonism. To gain insight into the mechanism of binding of the synthesized compounds, a tritiated antagonist, (R)-N(α)-diphenylacetyl-N(ω)-[2-([2,3-(3)H]propionylamino)ethyl]aminocarbonyl-(4-hydroxybenzyl)arginin-amide ([(3)H]UR-MK299, [(3)H]38), was prepared. [(3)H]38 revealed a dissociation constant in the picomolar range (Kd 0.044 nM, SK-N-MC cells) and very high Y1R selectivity. Apart from superior affinity, a considerably lower target off-rate (t1/2 95 min) was characteristic of [(3)H]38 compared to that of the higher homologue containing a tetramethylene instead of an ethylene spacer (t1/2 3 min, Kd 2.0 nM). Y1R binding of [(3)H]38 was fully reversible and fully displaceable by nonpeptide antagonists and the agonist pNPY. Therefore, the insurmountable antagonism observed in the functional assay has to be attributed to the extended target-residence time, a phenomenon of relevance in drug research beyond the NPY receptor field.
authors.forename: Max
authors.initials: M
authors.lastname: Keller
authors.forename: Stefan
authors.initials: S
authors.lastname: Weiss
authors.forename: Christoph
authors.initials: C
authors.lastname: Hutzler
authors.forename: Kilian K
authors.initials: KK
authors.lastname: Kuhn
authors.affiliation: CNRS/IPBS (Institut de Pharmacologie et Biologie Structurale) , 205 route de Narbonne, 31077 Toulouse cedex 5, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Mollereau
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dukorn
authors.forename: Lisa
authors.initials: L
authors.lastname: Schindler
authors.forename: Günther
authors.initials: G
authors.lastname: Bernhardt
authors.forename: Burkhard
authors.initials: B
authors.lastname: König
authors.forename: Armin
authors.initials: A
authors.lastname: Buschauer
mesh_terms: D000577:Amides; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000493:pharmacokinetics; D001667:Binding, Competitive; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004158:Diphenylacetic Acids / Q000493:pharmacokinetics*; D005456:Fluorescent Dyes; D016257:Fura-2; D006207:Half-Life; D006801:Humans; D007553:Isotope Labeling; D015335:Molecular Probes; D009478:Neuropeptide Y / Q000031:analogs & derivatives / Q000494:pharmacology; D019275:Radiopharmaceuticals / Q000493:pharmacokinetics*; D018013:Receptors, Neuropeptide / Q000187:drug effects; D017476:Receptors, Neuropeptide Y / Q000008:administration & dosage / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D004158:Diphenylacetic Acids; D005456:Fluorescent Dyes; D015335:Molecular Probes; C000605769:Nalpha-diphenylacetyl-Nomega-(propionylaminoethyl)aminocarbonyl-(4-hydroxybenzyl)argininamide; D009478:Neuropeptide Y; D019275:Radiopharmaceuticals; D018013:Receptors, Neuropeptide; D017476:Receptors, Neuropeptide Y; C083929:neuropeptide FF receptor; C097212:neuropeptide Y-Y1 receptor; D001120:Arginine; D016257:Fura-2