Cyclic analogues of bradykinin. IV. Structure-function relationships in the series of bradykinin cycloanalogues.
A study of the biological activity of six bradykinin and kallidin cycloanalogues has revealed that all of them exhibit prolonged hypotensive activity except the inactive cyclo-(omega-aminododecanoyl-omega-aminododecanoyl-bradykini n) (CADADB) when assayed in anaesthetized rats in vivo. The threshold dose of cyclo-bradykinin (CB) in these experiments was found to be 250 micrograms/kg of body weight. A single dose (500 micrograms/kg) of this cyclopeptide produces a decrease in the arterial pressure of rats up to 40 mm Hg for more than 2 h. The hypotensive action of other cyclopeptides under the same conditions is characterized by the following values: cyclo-[epsilon-(L-Lys1, Gly6)-bradykinin] (CLGB), alpha-L-Arg-cyclo-[epsilon-(L-Lys1, Gly6)-bradykinin] (ACLGB) and cyclo-epsilon-kallidin (CK) - 5 micrograms/kg, 40 mm Hg, over 2 h; cyclo-(omega-aminododecanoyl-bradykinin) (CADB) - 50 micrograms/kg, 250 micrograms/kg, 40 mm Hg, 35 min. Some cyclopeptides appeared to possess myotropic activity in vitro on isolated rat uterus preparations: CB (alpha = 0.52, pD2 = 7.86), CK (alpha = 1.0, pD2 = 7.56), CADB (alpha = 0.81, pD2 = 6.41). CLGB, ACLGB and CADADB failed to show myotropic activity. In contrast to CLGB and CADB, CK was hypotensive in dogs. CB acts as a weak antagonist of bradykinin (pA2 = 5.09 +/- 0.06) on rat uterus in vitro. It is believed that the hypotensive action within this series of compounds is primarily determined by the cycle size, whilst their myotropic activity is due to the presence of a "common" fragment Arg-Pro-Pro.(ABSTRACT TRUNCATED AT 250 WORDS)
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002942:Circular Dichroism; D004285:Dogs; D005260:Female; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D008297:Male; D008968:Molecular Conformation; D009119:Muscle Contraction / Q000187:drug effects; D051381:Rats; D013329:Structure-Activity Relationship; D014590:Uterine Contraction / Q000187:drug effects
D001920:Bradykinin