Red-fluorescent argininamide-type NPY Y1 receptor antagonists as pharmacological tools.

Fluorescently labelled NPY Y(1) receptor (Y(1)R) ligands were synthesized by connecting pyrylium and cyanine dyes with the argininamide-type Y(1)R antagonist core structure by linkers, covering a wide variety in length and chemical nature, attached to the guanidine group. The most promising fluorescent probes had Y(1)R affinities (radioligand binding) and antagonistic activities (calcium assay) in the one- to two-digit nanomolar range. These compounds turned out to be stable under assay conditions and to be appropriate for the detection of Y(1)Rs by confocal microscopy in live cells.

Bivalent argininamide-type neuropeptide y y(1) antagonists do not support the hypothesis of receptor dimerisation.

Bivalent ligands are potential tools to investigate the dimerisation of G-protein-coupled receptors. Based on the (R)-argininamide BIBP 3226, a potent and selective neuropeptide Y Y(1) receptor (Y(1)R) antagonist, we prepared a series of bivalent Y(1)R ligands with a wide range of linker lengths (8-36 atoms). Exploiting the high eudismic ratio (>1000) of the parent compound, we synthesised sets of R,R-, R,S- and S,S-configured bivalent ligands to gain insight into the "bridging" of two Y(1)Rs by simultaneous interaction with both binding sites of a putative receptor dimer.