NONPEPTIDE PEPTIDOMIMETIC ANTAGONISTS OF THE NEUROPEPTIDE-Y RECEPTOR - BENEXTRAMINE ANALOGS WITH SELECTIVITY FOR THE PERIPHERAL Y-2 RECEPTOR

We synthesized a new series of benextramine analogs as neuropeptide Y (NPY) functional group mimetics and tested them for N-[propionyl-H-3]NPY ([(3)]NPY) displacement activity in rat brain membrane homogenates and for NPY receptor antagonist activity in the rat femoral artery. The tetraamine, carbon analog N,N'-bis[6-[N-(2-naphthylmethyl)amino]hexyl]-1,6-hexanediamine (15) was equipotent with benextramine (based on comparison of the relevant IC50's) in a rat brain [H-3]NPY displacement assay, suggesting that the disulfide is not a necessary feature of benextramine's [H-3]NPY displacement activity, although this analog maintained selectivity for the benextramine-sensitive binding site population. The bis(N,N-dialkylguanyl) disulfide and carbon analogs 14a-c were 3-4 times more potent than their respective controls in displacing [H-3]NPY from rat brain membrane homogenates with IC(5)0's ranging from 15 to 18 mu M and maintained selectivity for the benextramine-sensitive, Y-1 binding site population. However, the activity of the carbon analog N,N'-bis[6-[N-(2-naphthylmethyl)amino]hexyl]-N,N'-(1,6-hexanediyl)diguanidine tetrahydrochloride (14b) showed a different profile in a femoral artery vasoconstriction assay; at 1.0 nM, this analog shifted the concentration-effect curve of the Y-2-selective agonist NPY13-36 to the right (pA(2) = 9.2; K-d = 0.63 nM) without a significant change in the maximum effect, while even at 1.0 mM it had no effect on the vasoconstrictive activity of the Y-1-selective agonist [Leu(31),Pro(34)]Npy. Thus, the bis(N,N-dialkylguanidine) analogs of benextramine are selective, competitive antagonists of the postsynaptic NPY receptor in the femoral artery.