Nonpeptide Peptidomimetic Antagonists of the Neuropeptide Y Receptor: Benextramine Analogs with Selectivity for the Peripheral Y2 Receptor
| Autor: | Michael B. Doughty, Chandra S. Chaurasia, G. A. Misse, Richard E. Tessel |
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| Rok vydání: | 1994 |
| Předmět: |
Male
Agonist medicine.medical_specialty Stereochemistry medicine.drug_class Molecular Sequence Data Population Cystamine Peptide hormone Rats Sprague-Dawley Structure-Activity Relationship Internal medicine mental disorders Drug Discovery medicine Animals Structure–activity relationship Neuropeptide Y Amino Acid Sequence Binding site education Adrenergic alpha-Antagonists education.field_of_study Chemistry Antagonist Biological activity Neuropeptide Y receptor humanities Rats Receptors Neuropeptide Y Endocrinology Molecular Medicine |
| Zdroj: | Journal of Medicinal Chemistry. 37:2242-2248 |
| ISSN: | 1520-4804 0022-2623 |
| DOI: | 10.1021/jm00040a018 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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