Aspartic acid scaffold in bradykinin B1 antagonists.
Several novel bradykinin B1 receptor (B1R) antagonists were synthesized utilizing a new aspartic acid scaffold. This core is derived from the highly potent dihydroquinoxalinone scaffold published recently by researchers at Merck (Ha et al. Biochem. Biophys. Res. Commun. 2005, 331, 159-166). Despite the considerably limited chemical space of B1 antagonists, the synthesized compounds still showed significant biological activity. None of the four most potent compounds showed significant activity on the bradykinin B2 receptor (B2R), consequently they can be considered as valuable starting points for designing more potent and selective B1 antagonists. Furthermore, the synthesis of these aspartic acid derivatives is much simpler than that of the original Merck compounds suggesting efficient parallel synthesis approaches during their optimization. Docking known and novel B1 antagonists into the refined B1R homology model including the second extracellular loop (EC2) underlined the importance of this loop in ligand binding. Comparative binding mode analysis revealed that our novel compounds bind similar to the dihydroquinoxalinone template. Our results indicate that the rigid core of the dihydroquinoxalinone containing B1 antagonists is not crucial for maintaining B1 activity.
Department of Medical Chemistry, University of Szeged, Dóm tér 8., H-6720, Szeged, Hungary. huszarjozsef@yahoo.com
József
J
Huszár
Zoltán
Z
Timár
Ferenc
F
Bogár
Botond
B
Penke
Róbert
R
Kiss
Krisztina Katalin
KK
Szalai
Eva
E
Schmidt
Andrea
A
Papp
György
G
Keseru
D000595:Amino Acid Sequence; D001224:Aspartic Acid / Q000031:analogs & derivatives / Q000737:chemistry*; D065169:Bradykinin B1 Receptor Antagonists; D003198:Computer Simulation; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid
D065169:Bradykinin B1 Receptor Antagonists; D001224:Aspartic Acid