| Autor: |
Sawada, Y., Kayakiri, H., Abe, Y., Mizutani, T., Inamura, N., Asano, M., Aramori, I., Hatori, C., Oku, T., Tanaka, H. |
| Zdroj: |
Journal of Medicinal Chemistry; May 2004, Vol. 47 Issue: 10 p2667-2677, 11p |
| Abstrakt: |
Introduction of various aliphatic amino groups at the 4-position of the quinoline moiety of our nonpeptide bradykinin (BK) B2 receptor antagonists afforded highly potent ligands for human B2 receptor with various affinities for guinea pig B2 receptor, indicating remarkable species difference. A representative 4-dimethyamino derivative 40a exhibited subnanomolar and nanomolar binding affinities for human and guinea pig B2 receptors, respectively, and significantly inhibited BK-induced bronchoconstriction in guinea pigs at 10 μg/kg by intravenous administration. Further chemical modification led us to discover unique partial agonists for the human B2 receptor that increase inositol phosphates (IPs) production by themselves in Chinese hamster ovary (CHO) cells expressing the cloned human B2 receptor. Although their potency and efficacy were much lower than those of BK, we identified them as screening leads for nonpeptide B2 agonists. In these studies it was revealed the 4-substituent of the quinoline moiety is the key pharmacophore to determine species difference and agonist/antagonist profiles. |
| Databáze: |
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