Bradykinin receptor antagonists containing N-substituted amino acids: in vitro and in vivo B(2) and B(1) receptor antagonist activity.

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