New highly potent bradykinin B2 receptor antagonists.
pA2 values of new B2 receptor antagonists ranging from 7.51 to 8.86 were measured on the rabbit jugular vein, while lower values were observed in the other preparations (for instance, the hamster urinary bladder). The most potent antagonists were those containing a hydroxyproline (Hyp) in position 3, a D-Arg at the N-terminal and a Leu instead of a Phe in position 8, with or without other chemical changes. D-Arg[Hyp3,D-Phe7,Leu8]-BK was found to be competitive, selective for B2 receptors and specific for kinins since it was without effect against substance P and angiotensin II in the rabbit jugular vein. The essential feature for obtaining B2 receptor antagonists appears to be the replacement or reorientation of Phe8 of bradykinin. The rabbit jugular vein provides a sensitive bioassay in which the potency and specificity of B2 receptor antagonists can be adequately evaluated.
Regoli
D
D
Department of Pharmacology, Medical School, University of Sherbrooke, Quebec, Canada.
Rhaleb
N E
NE
Tousignant
C
C
Rouissi
N
N
Nantel
F
F
Jukic
D
D
Drapeau
G
G
D000595:Amino Acid Sequence; D000818:Animals; D001920:Bradykinin / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D009130:Muscle, Smooth / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D011817:Rabbits; D018002:Receptors, Bradykinin; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors*; D014132:Trachea / Q000187:drug effects; D001743:Urinary Bladder / Q000187:drug effects
D018002:Receptors, Bradykinin; D017981:Receptors, Neurotransmitter; C073117:bradykinin, Arg-Hyp(3)-Phe(7)-Leu(8)-; D001920:Bradykinin