Bradykinin receptor antagonists containing N-substituted amino acids: in vitro and in vivo B(2) and B(1) receptor antagonist activity
Autor: | David K. Cuadrado, Wendy L. Hanson, Val S. Goodfellow, Maciej Wieczorek, Timothy D. Fitzpatrick, Sherman E. Ross, Manoj V. Marathe, Eric T. Whalley, Karen G. Kuhlman, Michael Burkard, John S. Zuzack |
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Rok vydání: | 1996 |
Předmět: |
medicine.medical_specialty
Magnetic Resonance Spectroscopy Arginine Receptor Bradykinin B2 Guinea Pigs Molecular Sequence Data Bradykinin Blood Pressure Pharmacology Receptor Bradykinin B1 Binding Competitive Mass Spectrometry chemistry.chemical_compound Structure-Activity Relationship In vivo Ileum Internal medicine Drug Discovery medicine Potency Animals Humans Amino Acid Sequence Amino Acids Receptor Aorta Bradykinin Receptor Antagonists Molecular Structure Chemistry Receptors Bradykinin Uterus Antagonist In vitro Rats Endocrinology Molecular Medicine Female Rabbits Oligopeptides Receptor antagonist activity Protein Binding |
Zdroj: | Journal of medicinal chemistry. 39(7) |
ISSN: | 0022-2623 |
Popis: | We report a systematic probing of the structural requirements of the bradykinin (BK) type 2 (B(2)) receptor for antagonist activity by incorporating N-alkyl-amino acid residues at positions 7 and 8 of a potent antagonist sequence. Compound 1 (D-Arg(0)-Arg(1)-Pro(2)-Hyp(3)-Gly(4)-Thi(5)-Ser(6)-D-Tic(7)-N-Chg (8)-Arg(9), CP-0597)(1,2) is a potent (pA(2) = 9.3, rat uterus; pK(i) = 9.62, binding, human receptor clone) B(2) receptor antagonist devoid of in vitro B(1) antagonist activity (rabbit aorta). Compound 1 exhibits high potency (ED(50) = 29.2 pmol/kg/min, iv, rabbit) and duration of action when tested in models for in vivo B(2) antagonist activity. Although devoid of activity in a classic B(1) isolated tissue assay, B(1) antagonist activity for 1 was demonstrated in vivo, in a LPS-treated, inducible BK(1) receptor rabbit blood pressure model (ED(50) = 1.7 nmol/kg/min). D-Arg(0) of 1 can be formally replaced by an achiral arginine surrogate, without significant loss in antagonist potency on rat uterus (compound 11, B(2) pA(2) = 9.1). Antagonist 13 (Hyp(2), Nchg(8)), pK(i) = 10.2, and agonist 4 (N-methylcyclohexyl-Gly(8)), pK(i) = 10.1, also exhibited substantial binding to guinea pig ileum membrane receptors as well as a human B(2) receptor clone. Very minor structural changes in the N-alkyl amino acid residues in positions 7 and 8 can modify the activity of this class of compounds from being extremely potent antagonists to tight binding partial or full agonists. These studies have resulted in a series of compounds containing inexpensive amino acid residues but which produce broad spectrum BK receptor blocking potency and exceptional in vivo duration of action. |
Databáze: | OpenAIRE |
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