Effects of the non‐peptide B2 antagonist FR173657 on kinin‐induced smooth muscle contraction and relaxation, vasoconstriction and prostaglandin release
Authors: Griesbacher Thomas , Sametz Wolfgang , Legat Franz J. , Diethart Sabine , Hammer Susanne , Juan Heinz 
Published: July 2006

The non‐peptide bradykinin (BK) antagonist (E)‐3‐(6‐acetamido‐3‐pyridyl)‐N‐[N‐[2,4‐dichloro‐3‐[(2‐ methyl‐8‐quinolinyl)oxymethyl]phenyl]‐N‐methylaminocarbonylmethyl]acrylamide (FR173657) was tested in intestinal, uterine, tracheal and vascular in vitro preparations. The investigation aimed at determining the antagonistic potency, duration of action, specificity for BK receptors and apparent mode of antagonistic action of FR173657.

Contractions of the isolated ileum of the guinea‐pig in response to BK were inhibited by FR173657 (10–300 nM) in a concentration‐dependent manner. The inhibition lasted for up to 90 min after wash‐out of FR173657. Cumulative concentration‐response curves to BK were shifted to the right with a concomitant decrease in the maximum effect. A pKB value of 8.7 was determined. FR173657 had no effect on contractions induced by acetylcholine, histamine, 5‐hydroxytryptamine, substance P, angiotensin II or caerulein.

The concentration‐response curves for B2 receptor‐mediated relaxations of the rat isolated duodenum induced by BK were shifted to the right together with a concomitant reduction of the maximum BK effect in the presence of FR173657 (10–300 nM). A pKB of 9.0±0.2 was calculated. FR173657 had no effect on B1 receptor‐mediated relaxations in response to des‐Arg9‐BK.

The concentration‐response curves for BK‐induced contractions of the rat isolated uterus were shifted to the right by FR173657 (3–300 nM) in a concentration‐dependent and parallel manner. The Schild plot for the inhibition caused by FR173657 had a slope of −0.98 indicating a competitive mode of antagonism. A pA2 value of 9.1 was determined.

Contractions of the circular smooth muscles of the guinea‐pig isolated trachea in response to BK were concentration‐dependently inhibited by FR173657 (10–100 nM). An affinity estimate of 9.3 was calculated for FR173657. Contractions induced by acetylcholine and relaxations in response to isoprenaline remained completely unaffected by FR173657.

In the rabbit isolated perfused ear, BK (0.01–10 nmol) produced a dose‐dependent vasoconstriction. In the presence of 30 nM FR173657, the effects of BK were reduced by at least 60%, while FR173657 completely abolished the effects of all BK doses at 300 nM. FR173657 did not affect vasoconstriction induced by noradrenaline or angiotensin II.

The arterial injection of BK (10 nmol) into the rabbit isolated perfused ear caused an approximately three fold increase in the release of the prostaglandins E2 and I2 into the venous effluent. The BK‐stimulated prostaglandin release was completely abolished in the presence of FR173657 (300 nM) while the basal prostaglandin release was unchanged.

In summary, FR173657 was shown to be a highly potent and selective BK antagonist which was active on B2, but not B1, receptors. FR173657 was a competitive antagonist in the rat uterus but showed a deviation from competitive inhibition in the other preparations studied similar to other second generation peptide antagonists. The inhibitory action in vitro was long‐lasting, but was fully reversible.