1,3-Disubstituted benzazepines as novel, potent, selective neuropeptide Y Y1 receptor antagonists
| Autor: | Makoto Kii, Michiko Ishikawa, Shin-ichi Mihara, Hirokazu Hara, Kohji Hanasaki, Sanji Hagishita, Tetsuo Okada, Yasushi Murakami, Mayumi Shimamura, Goro Kato, Masafumi Fujimoto, Hiroshi Hashizume, Yasunobu Ishihara |
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| Rok vydání: | 1999 |
| Předmět: |
Stereochemistry
CHO Cells Chemical synthesis Histamine Release Benzazepine chemistry.chemical_compound Radioligand Assay Structure-Activity Relationship Cricetinae Drug Discovery Tumor Cells Cultured Animals Humans Benzothiazoles Guanidine Bicyclic molecule Phenylurea Compounds Antagonist Benzazepines Neuropeptide Y receptor Rats Receptors Neuropeptide Y chemistry Peptide YY Lactam Molecular Medicine Calcium |
| Zdroj: | Journal of medicinal chemistry. 42(14) |
| ISSN: | 0022-2623 |
| Popis: | A novel series of potent and selective non-peptide neuropeptide Y (NPY) Y1 receptor antagonists, having benzazepine nuclei, have been designed, synthesized, and evaluated for activity. Chemical modification of the R(1) and R(3) substituents in structure 1 (Chart 1) yields several compounds that show high affinity for the Y1 receptor (K(i) values of less than 10 nM). SAR studies revealed that introduction of an isopropylurea group at R(1) and a 3-(benzo-condensed-urea) group, 3-(fluorophenylurea) group, or a 3-(N-(4-hydroxyphenyl)guanidine) group at R(3) in structure 1 afforded potent and subtype-selective NPY Y1 receptor antagonists. 3-(3-(Benzothiazol-6-yl)ureido)-1-N-(3-(N'-(3-isopropylureido++ +))benzyl )-2,3,4,5-tetrahydro-1H-1-benzazepin-2-one (21), which was one of the most potent derivatives, competitively inhibited specific [(125)I]peptide YY (PYY) binding to Y1 receptors in human neuroblastoma SK-N-MC cells (K(i) = 5.1 nM). 21 not only inhibited the Y1 receptor-mediated increase in cytosolic free Ca(2+) concentration in SK-N-MC cells but also antagonized the Y1 receptor-mediated inhibitory effect of peptide YY on gastrin-induced histamine release in rat enterochromaffin-like cells. 21 showed no significant affinity in 17 receptor binding assays including Y2, Y4, and Y5 receptors. |
| Databáze: | OpenAIRE |
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