title: Nonpeptide peptidomimetic antagonists of the neuropeptide Y receptor: benextramine analogs with selectivity for the peripheral Y2 receptor.
abstract: We synthesized a new series of benextramine analogs as neuropeptide Y (NPY) functional group mimetics and tested them for N-[propionyl-3H]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 [3H]NPY displacement assay, suggesting that the disulfide is not a necessary feature of benextramine's [3H]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 [3H]NPY from rat brain membrane homogenates with IC50's ranging from 15 to 18 microM and maintained selectivity for the benextramine-sensitive, Y1 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 Y2-selective agonist NPY13-36 to the right (pA2 = 9.2; Kd = 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 Y1-selective agonist [Leu31,Pro34]NPY. Thus, the bis(N,N-dialkylguanidine) analogs of benextramine are selective, competitive antagonists of the postsynaptic NPY receptor in the femoral artery.
authors.affiliation: Department of Medicinal Chemistry, University of Kansas, Lawrence 66045.
authors.forename: C
authors.initials: C
authors.lastname: Chaurasia
authors.forename: G
authors.initials: G
authors.lastname: Misse
authors.forename: R
authors.initials: R
authors.lastname: Tessel
authors.forename: M B
authors.initials: MB
authors.lastname: Doughty
mesh_terms: D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000595:Amino Acid Sequence; D000818:Animals; D003538:Cystamine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D008969:Molecular Sequence Data; D009478:Neuropeptide Y / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017476:Receptors, Neuropeptide Y / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D000317:Adrenergic alpha-Antagonists; D009478:Neuropeptide Y; D017476:Receptors, Neuropeptide Y; C029998:benextramine; D003538:Cystamine