Design and Synthesis of Potent Bradykinin Agonists Containing a Benzothiazepine Moiety
| Autor: | Jean Martinez, Pierre Bélichard, Jean-Luc Paquet, Pierre Dodey, Didier Pruneau, Gilbert Bergé, Isabelle Daffix, Philippe Bedos, Muriel Amblard, Jean-Michel Luccarini |
|---|---|
| Rok vydání: | 1999 |
| Předmět: |
Receptor
Bradykinin B2 Stereochemistry Inositol Phosphates Bradykinin Angiotensin-Converting Enzyme Inhibitors CHO Cells In Vitro Techniques Receptor Bradykinin B1 Transfection Chemical synthesis Muscle Smooth Vascular Umbilical vein Umbilical Cord Rats Sprague-Dawley Radioligand Assay Uterine Contraction chemistry.chemical_compound Cricetinae Drug Discovery Peptide synthesis Animals Humans Moiety Cloning Molecular Bradykinin receptor Dipeptide Receptors Bradykinin Biological activity Rats chemistry Drug Design Molecular Medicine Female Muscle Contraction |
| Zdroj: | Journal of Medicinal Chemistry. 42:4185-4192 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | A bradykinin analogue (H-Arg-Pro-Pro-Gly-Phe-Ser-D-BT-Arg-OH, 3) in which the Pro-Phe dipeptide was replaced by the (3S)[amino]-5-(carbonylmethyl)-2,3-dihydro-1, 5-benzothiazepin-4(5H)-one (D-BT) moiety has been synthesized. The same modification was performed on the potent bradykinin B(2) receptor antagonist HOE 140 (H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg-OH), in which the -D-Tic-Oic- moiety was replaced by D-BT to yield H-D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-BT-Arg-OH, 1 (JMV1116). These compounds were examined in vitro for their binding affinity toward bradykinin B(1) and B(2) receptors as well as for their ability to interfere with bradykinin-induced contraction of both human umbilical vein and rat uterus. The two compounds 3 and 1 competed with [(3)H]bradykinin binding to the human cloned B(2) receptor giving K(i) values of 13 +/- 2 and 0.7 +/- 0.1 nM, respectively. Unexpectedly, both compounds were full bradykinin B(2) receptor agonists on the human umbilical vein (pD(2) = 6.60 +/- 0.07 for 3 and 6.80 +/- 0.08 for 1) and rat uterus (pD(2) = 7.20 +/- 0.09 for 3 and 7.50 +/- 0.09 for 1) preparations with the same efficacy as bradykinin. In addition 1 induced a concentration-dependent phosphoinositide production in CHO cells expressing the human cloned B(2) receptor. These data provide evidence for a bioactive conformation of bradykinin constrained at the dipeptide Pro-Phe. |
| Databáze: | OpenAIRE |
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