Highly Selective Bradykinin Agonists and Antagonists with Replacement of Proline Residues by N-Methyl-d- and l-phenylalanine

• Published in: Journal of medicinal chemistry Vol. 39; no. 4; pp. 929 - 936
• Main Authors: Reissmann, Siegmund, Schwuchow, Carola, Seyfarth, Lydia, De Castro, Luis Felipe Pineda, Liebmann, Claus, Paegelow, Inge, Werner, Heinz, Stewart, John M
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 16.02.1996; Amer Chemical Soc
• Subjects: Amino Acid Sequence; Animals; Bradykinin - agonists; Bradykinin - analogs & derivatives; Bradykinin - antagonists & inhibitors; Bradykinin - chemical synthesis; Cell Membrane - metabolism; Chemistry, Medicinal; Female; Guinea Pigs; Ileum - drug effects; Ileum - physiology; In Vitro Techniques; Indicators and Reagents; Life Sciences & Biomedicine; Male; Molecular Sequence Data; Muscle, Smooth - drug effects; Muscle, Smooth - physiology; Pharmacology & Pharmacy; Phenylalanine - analogs & derivatives; Proline; Protein Conformation; Rats; Receptors, Bradykinin - drug effects; Receptors, Bradykinin - metabolism; Science & Technology; Stereoisomerism; Structure-Activity Relationship; Uterus - drug effects; Uterus - physiology; DESIGN; PAIN; PEPTIDES; RECEPTOR ANTAGONISTS; ANALOGS; MEMBRANES; KININS; CONFORMATIONAL-ANALYSIS; PROTON MAGNETIC-RESONANCE; HORMONE-RELEASING HORMONE
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm9301954

For further studies on the structural and conformational requirements of positions 2, 3, and 7 in the bradykinin sequence, we replaced the proline residues by the more hydrophobic and conformationally restricted N-methyl-l- and d-phenylalanine (NMF). The biological activities of the new analogs were evaluated on rat uterus, guinea pig ileum, and guinea pig lung strip. Receptor binding of the analogs was studied in membranes from rat uterus and guinea pig ileum. Influence of bradykinin analogs on the release of cytokines from mouse spleen cell cultures was also measured. Bradykinin analogs were synthesized by the solid phase method, using Boc strategy on PAM or Merrifield resins. The best results in the formation of the N-methylamide bond were obtained with the coupling reagent PyBrop. In position 7 the substitution of d-Phe by d-NMF, retaining the configuration of the amino acid, converts bradykinin antagonists into agonists. The bradykinin analogs with d-NMF at position 7 gave the highest known tissue selectivity for rat uterus among agonists. [l-NMF2]bradykinin has moderate agonist activity on rat uterus but antagonist activity on guinea pig lung strip. It represents a new antagonist for B2 receptors without any replacement at position 7. The same analog completely inhibits bradykinin-evoked cytokine expression by mononuclear cells.