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J Med Chem. 2000 Jun 15;43(12):2382-6.

Synthesis and biological evaluation of bradykinin B(1)/B(2) and selective B(1) receptor antagonists.

Author information

1
Laboratoire des Aminoacides Peptides et Protéines, UMR5810-CNRS, Universités Montpellier I et II, Faculté de Pharmacie, 15 Av. C. Flahault, 34060 Montpellier Cédex, France.

Abstract

We recently described a potent bradykinin B(2) receptor agonist (JMV1116) obtained by replacing the D-Tic-Oic dipeptide moiety of HOE140 by a (3S)-amino-5-(carbonylmethyl)-2,3-dihydro-1, 5-benzothiazepin-4(5H)-one (D-BT) moiety. This compound inhibited the specific binding of [(3)H]BK on membranes of CHO cells expressing the human cloned B(2) receptor with nanomolar affinity and contracted both isolated rat uterus and human umbilical vein. These data demonstrated that D-BT could be a good mimic of the Pro-Phe dipeptide. In the present study we characterized B(1) receptor antagonists containing the D-BT moiety. We prepared an analogue of compound JMV1116 deleting the C-terminal arginine residue. The resulting compound (1) had an affinity of 83 nM for the human cloned B(1) receptor. The most remarkable property of 1 is its ability to bind also the B(2) receptor with an affinity of 4.4 nM despite the absence of the C-terminal arginine residue. Modifications at the N-terminal part of 1 associated with the substitution of the thienylalanine residue by alpha-(2-indanyl)glycine resulted in analogues selectively binding to the B(1) receptor with an affinity in the picomolar range.

PMID:
10882364
DOI:
10.1021/jm990961s
[Indexed for MEDLINE]

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