Bradykinin competitive antagonists for classical kinin systems.
The substitution of D-phenylalanine for proline at position 7 of bradykinin (BK) converts BK into a specific antagonist. Additional modifications of the nonapeptide structure, especially the inclusion of beta-2-thienylalanine residues (Thi) for phenylalanine at positions 5 and 8, increase antagonist potency in the classic smooth muscle (isolated rat uterus and guinea pig ileum) and rat blood pressure kinin assays. [Thi5,8,DPhe7]-BK had a pA2 value of 6.5 for inhibition of the BK response on rat uterus, and 6.3 on guinea pig ileum. Addition of Lys-Lys- or a D-Arg- residue to the N-terminal of D-Phe7-substituted antagonists decreases uterine agonist activity, but does not affect inhibitory potency on the ileum. Addition of a D-proline residue in place of proline in position 3 of D-Arg- extended antagonists produces specific uterine inhibitors which show no antagonism on the ileum. The D-Phe7-analogs did not inhibit smooth muscle responses to substance-P or angiotensin-II, and the antagonism of kinin responses was competitive.
D000596:Amino Acids; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005260:Female; D006168:Guinea Pigs; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010649:Phenylalanine; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014590:Uterine Contraction / Q000187:drug effects
D000596:Amino Acids; D010649:Phenylalanine; D001920:Bradykinin