Zusammenfassung
Analogues of the argininamide-type NPY Y-1 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 ...
Zusammenfassung
Analogues of the argininamide-type NPY Y-1 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-a-diphenylacetyl-N-omega-[2-([2,3-H-3]propionylamino)ethyl]aminocarbonyl-(4-hydroxybenzyl)arginin-amide ([H-3]UR-MK299, [H-3]38), was prepared. [H-3]38 revealed a dissociation constant in the picomolar range (K-d 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 [H-3]38 compared to that of the higher homologue containing a tetramethylene instead of an ethylene spacer (t(1/2) 3 min, K-d 2.0 nM). Y1R binding of [H-3]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.
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