Collect. Czech. Chem. Commun. 2011, 76, 763-780
Published online 2011-05-31 10:13:31

Synthesis and characterization of DMAP-modified NPY Y1 receptor antagonists as acyl-transfer catalysts

Stefan Weissa, Günther Bernhardtb, Armin Buschauerb and Burkhard Königa,*

a Institut für Organische Chemie, Universität Regensburg, D-93040 Regensburg, Germany
b Institut für Pharmazie, Universität Regensburg, D-93040 Regensburg, Germany


Starting from the working hypothesis that specific chemical labelling may be an attractive approach to detect and study G protein-coupled receptors (GPCRs) we synthesized catalytically active antagonists of the neuropeptide Y1 receptor (Y1R). An argininamide-type Y1R antagonist scaffold was combined with a DMAP moiety via spacers of different length and chemical nature. These hybrid compounds have Y1R affinities in the two-digit nanomolar range and are capable of catalysing acyl-transfer reaction to surrogates of bionucleophiles, as demonstrated in the absence of cells by using esters of fluorescent dyes as substrates in buffer. By contrast, selective staining of Y1Rs on living MCF-7 cells was not achieved due to significant non-catalysed (Y1R ligand independent) reaction with biomolecules and the limited density of Y1R on the cell surface. Although this may also depend on insufficient selectivity of the staining reagents, the results of this study suggest that the general applicability of catalytic staining to GPCRs has to be reconsidered, as this approach is hampered by a very low portion of receptor of interest compared to the total amount of membrane proteins.

Keywords: Medicinal chemistry; Acylation; Molecular recognition; Neuropeptide Y; Antagonist.

References: 28 live references.