(Hypertension. 1997;29:951-956.)
© 1997 American Heart Association, Inc.
Articles |
FR 173657: A New, Potent, Nonpeptide Kinin B2 Receptor Antagonist
An In Vitro Study
From the Institute of Pharmacology, University of Ferrara (Italy) (A.R., G.C., D.R.,); Department of Pharmacology, Medical School, University of Sherbrooke (Canada) (F.G.); and Fujisawa Pharmaceutical Co, Osaka, Japan (N.I.).
Correspondence to Prof Domenico Regoli, Institute of Pharmacology, University of Ferrara, Via Fossato di Mortara, 17-19, 44100 Ferrara, Italy. E-mail fmc{at}ifeuniv.unife.it
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Abstract |
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Abstract FR 173657, the first effective nonpeptide kinin B2 receptor antagonist, has been tested in four preparations from different species (human, pig, rabbit, and guinea pig). The new compound shows high apparent affinity for the four B2 receptors, with pA2 values ranging from 8.2 to 9.4. FR 173657 is a selective B2 receptor antagonist that does not interact with human, pig, or rabbit B1 receptors. The new compound is extremely specific for the kinin B2 receptors as it does not affect the myotropic effects of norepinephrine, endothelin-1, or 5-hydroxytryptamine in the human umbilical vein; the contractions elicited by substance P and angiotensin II in the rabbit jugular vein or those produced by acetylcholine and histamine in the guinea pig ileum; or the relaxation of the pig coronary artery induced by norepinephrine and substance P. FR 173657 acts as a competitive antagonist over an extended range of concentrations on human and rabbit B2 receptors, whereas on pig and guinea pig receptors, it depresses the maximal effect of bradykinin and thus appears to act as a noncompetitive antagonist.
Key Words: FR 173657 • receptors, bradykinin • blood vessels • species specificity • biological assay
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Introduction |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Because of the important role kinins play in inflammation and nociception,1 2 the search of antagonists for the kinin receptors has been pursued for many years. Regarding the kinin B2 receptor, the discovery by Vavrek and Stewart3 of peptidic analogues such as [D-Phe7]-BK or [Thi5,8,D-Phe7]-BK defined the starting point for the development of potent and selective antagonists. The prototype of these antagonists has become Hoe 140 (D-Arg,[Hyp3,Thi5,D-Tic7,Oic8]-BK).4 Hoe 140 is a relatively long-acting compound that has been found to antagonize BK in animal4 5 and human6 7 8 tissues and has provided an essential tool for the study of the potential roles of kinins in physiology and physiopathology. However, Hoe 140 is considerably limited in its therapeutic potential because it is still a relatively large molecule of peptidic nature. Nonpeptide receptor antagonists that can be administered orally and possess the favorable features required for application in the clinic have still not been discovered. The report that WIN 64338 is "a potent B2 receptor antagonist in human tissues"9 has not been confirmed.8 The Winthrop compound is now considered as an early unsuccessful attempt.
A new nonpeptide antagonist for the B2 receptor has been recently identified by scientists at Fujisawa.10 11 FR 173657 has been found to compete specifically and selectively with the binding of [3H]BK to guinea pig B2 receptors (ileum and lung) and to human B2 receptors expressed in A431, WI38, and IMR-90 cell lines as well as to prevent bronchoconstriction induced in the guinea pig by BK or dextran sulfate.11 We have used this compound in the present investigation to inhibit B2 receptor–mediated contractile or relaxing effects of kinins in several species, including humans. The principal aims of this study were (1) to describe the pharmacodynamic features of FR 173657 as an antagonist of human, pig, rabbit, and guinea pig B2 receptors and (2) to compare the pharmacological profile of FR 173657 with that of Hoe 140,4 the "reference" B2 receptor antagonist.
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Methods |
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Tissue Preparations
Handling of animals and experiments on hUV were made in accord with the guidelines of the Ethics Committee of the Medical School of the University of Ferrara (Italy). Human umbilical cords from healthy women 22 to 40 years old were collected after spontaneous delivery at term and placed in cold (4°C) Krebs' solution. The lapse of time between delivery and the experiment averaged 4 hours (range, 1 to 10 hours). In the laboratory, the middle segment of the cord (7 to 8 cm long) was placed in Krebs' solution at room temperature, and within 30 minutes, the hUV was dissected free of surrounding tissue and cut into spiral strips (20 mm long, 3 mm wide). The endothelium was rubbed off with a cotton swab. The pig vessels (from adult pigs weighing 160 kg) were obtained from the Negrini slaughterhouse and placed in cold (4°C) Krebs' solution. In the laboratory (about 1 to 1.5 hours after the animal's death), the left anterior descending pCA was cut into rings (10 mm wide) with preserved endothelium. The pRV was cut into open rings and the endothelium removed. New Zealand White rabbits (1.3 to 1.8 kg) and Dunkin-Hartley guinea pigs (250 to 300 g) of either sex were killed by stunning and exsanguination. Tissues were prepared according to the procedures previously described by Gaudreau et al12 for the rbJV, by Furchgott and Bhadrakom13 for the rbA, and by Rang14 for the gpI.
All tissues were suspended in 10-mL organ baths containing warm (37°C), oxygenated (95% O2/5% CO2) Krebs' solution of the following composition (mmol/L): NaCl 118.1, KCl 4.7, CaCl2 2.5, KH2PO4 1.2, MgSO4 1.2, NaHCO3 25, and glucose 10. The hUV, pCA, pRV, and rbA were stretched to a resting tension of 2 g, and the rbJV and gpI were loaded with 0.5 g. Changes of tension were measured isometrically with force transducers (FT03, Grass Instruments) and recorded on multichannel chart recorders (Grass model 7D or Linseis GmbH model L2005). In all experiments, the kininase II inhibitor captopril (Squibb) was added to the Krebs' solution at a concentration of 1 µmol/L.
Experimental Protocols
Before any agent was tested, the human tissues were allowed to
equilibrate for 90 to 120 minutes and the resting tension was
readjusted every 15 minutes. The experiments began with the application
of 30 mmol/L KCl for measurement of preparation responsiveness.
The same equilibration time was allowed for the other tissues.
The B2 receptor agonist BK was used as standard agonist in the rbJV, gpI, pCA, and hUV. This latter tissue, pretreated with Lys-[Leu8]-des-Arg9-BK (1 µmol/L) to eliminate the interference of B1 receptor,8 will be indicated as hUV°. Since the B2 receptor of the pCA is primarily a relaxing one,15 this tissue was brought to contraction by about 4 g with acetylcholine (1 µmol/L) before application of BK.
The B1 receptor agonist Lys-des-Arg9-BK was used in the rbA, pRV, and hUV. This latter tissue, pretreated with Hoe 140 (1 µmol/L) to eliminate the interference of B2 receptor,8 will be indicated as hUV*. In these preparations, we applied Lys-des-Arg9-BK (10 nmol/L) 1, 3, and 5 hours after the beginning of the equilibration period to assess the progressive increase of tissue responses to B1 agonists, which reaches its maximum after 6 to 7 hours.8 16
We evaluated the antagonistic activity of FR 173657, Hoe 140, WIN 64338, and Lys-[Leu8]-des-Arg9-BK in terms of pA2 by measuring cumulative concentration-response curves of BK or Lys-des-Arg9-BK in the absence and presence of increasing concentrations of the antagonists to collect the experimental data for Schild plots. The antagonists were applied 30 minutes before the standard agonist, which was BK in the B2 receptor preparations (hUV°, pCA, rbJV, and gpI) and Lys-des-Arg9-BK in the B1 receptor systems (hUV*, rbA, and pRV).
Selectivity of the antagonist for the B2 receptor was evaluated by testing 1 µmol/L FR 173657 against Lys-des-Arg9-BK in the B1 receptor preparations.
Several agents (acetylcholine, substance P, histamine, angiotensin II, 5-hydroxytryptamine, norepinephrine, and endothelin-1) mediating contraction or relaxation of the various tissues were used. The myotropic activity or relaxing effect of each agent (given at a submaximal concentration) was challenged with 1 µmol/L FR 173657 to assess the specificity of the antagonist for the kinin B2 receptor.
Agents and Drugs
All kinin receptor agonists and antagonists as well as substance
P and angiotensin II were prepared by solid-phase synthesis and
purified by high-performance liquid chromatography, as previously
described by Drapeau and Regoli.17 Abbreviations of
nonnatural residues are as follows: Hyp:
trans-4-hydroxy-L-proline; D-Tic:
L-(1,2,3,4-tetrahydro-isoquinoline-3-carboxylic acid); and
Oic: L-(3aS,
7aS)-octahydro-indol-2-carboxylic acid. Hoe
1404 was made available by Hoechst AG; WIN 64338
(phosphonium,[[4-[[2[[bis(cyclohexylamino)methylene]amino]-3-(2-naphthylenyl)-1-oxopropyl]-amino]phenyl]
methyl]tributyl,chloride, monohydrochloride)9 was
supplied by Sterling Winthrop. FR 173657 (see chemical structure in Fig 1
)
[(E)-3-(6-acetamido-3-pyridyl)-N-(N-{2,4-dichloro-3-[(2-methyl-8-quinolinyl)oxymethyl]phenyl}-N-methyl)
aminocarbonyl methyl)acrylamide]11 was a gift of
Fujisawa.
Captopril([2S]-1-[3-mercapto-2-methylpropionyl]-L-proline) was
obtained from Squibb. Mergetpa
(DL-2-mercaptomethyl-3-guanidinoethyl propanoic acid)
was purchased fromCalbiochem-Boehringer. All other agents,
norepinephrine, 5-hydroxytryptamine, histamine, and all reagents
were from Sigma Chemical Co or E Merck. Concentrated solutions (1
mmol/L) of peptides and other agents were made in double-distilled
water or isotonic saline and kept at -20°C. Solutions of WIN 64338
and FR 173657 were made in dimethyl sulfoxide (final concentration in
the organ baths not exceeding 0.1%).
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Data Analysis and Terminology
All data presented in the figures are expressed as mean±SE.
Data presented in Figs 2 and 3 were statistically analyzed with one-way
ANOVA plus the Newman-Keuls correction for multiple comparisons; data
presented in Fig 4 were statistically analyzed with Student's
t test for unpaired data. Statistical analysis was performed
with a software package.18 Values of P<.05
were considered to be significant.
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indicates control; 
, 10 nmol/L; 
, 100
nmol/L; and *, 1000 nmol/L). Values are mean±SE of at least
eight experiments. b, Schild plot of FR 173657 against BK in hUV°. c,
Concentration-response curves of BK obtained in pCA precontracted with
1 µmol/L acetylcholine in the absence and presence of increasing
concentrations of FR 173657 (
, 1
nmol/L;
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, 84 nmol/L; and
*, 840 nmol/L). Values are mean±SE of at least seven
experiments. **P<.01 vs control, ANOVA plus Newman-Keuls
correction for multiple comparisons. d, Schild plot of FR 173657
against BK in gpI.
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The pharmacological terminology adopted in this article is in line with recent recommendations of the International Union of Pharmacology.19 20 The agonist apparent affinities are given as pEC50 (the negative logarithm to base 10 of the molar concentration of an agonist that produces 50% of the maximal possible effect). Antagonist affinities are given in terms of pA2 (the negative logarithm to base 10 of the molar concentration of an antagonist that makes it necessary to double the concentration of agonist needed to elicit the original submaximal response).19 21 The pA2 values were obtained from Schild plots according to Arunlakshana and Schild.22
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Results |
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Affinities of Kinin Receptor Agonists
Results obtained in the present and previous studies with kinin agonists (four naturally occurring peptides) acting as stimulants or inhibitors (only in the pCA) of vascular (hUV, pCA, rbJV, rbA, and pRV) or intestinal (gpI) smooth muscles are presented in the Table
. The myotropic contractile or relaxing effects
obtained in the first four tissues were mediated by B2
receptors because they were evoked by kinins (BK and Lys-BK) and not by
the C-terminal des-Arg metabolites. The responses of the other three
preparations were due to the activation of B1 receptors
because des-Arg9-BK and Lys-des-Arg9-BK are
active, whereas BK and Lys-BK are inactive. pEC50 values
obtained with BK and Lys-BK in the three vascular preparations (hUV°,
pCA, and rbJV) were similar, whereas pEC50 measured in the
intestinal smooth muscle (gpI) was slightly lower. Very similar
pEC50 values were measured with Lys-des-Arg9-BK
in the three B1 receptor systems (hUV*, rbA, and pRV).
pEC50 values for des-Arg9-BK showed differences
(not greater than 0.5 log unit) between the human (6.8) and rabbit
(7.3) receptor, in accord with Menke et al23 and Gobeil et
al.8
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Affinities of Kinin Receptor Antagonists
Concentration-response curves obtained with BK in the absence and
presence of increasing concentrations of FR 173657 in the four
B2 receptor systems are presented in Figs 2
and 3. The hUV* responded to BK with a strong
contraction that reached 6 g (Fig 2a). The concentration-response
curves of BK measured in the presence of FR 173657 (10, 100, and 1000
nmol/L) were displaced to the right, maintained parallelism, and
reached full maximal effects. The Schild plot (Fig 2b) was linear,
showing a slope of 0.98; the extrapolated pA2 value was
8.22. Moreover, in the hUV*, the antagonistic effect of FR 173657
against BK was reversible. In fact, the contractile effect of BK was
fully recovered after 90 minutes of washing out the compound (data not
shown).
In the pCA (stimulated by 1 µmol/L acetylcholine), which
responds to BK with a concentration-dependent relaxation (Fig 2c), the
concentration-response curves obtained in the presence of the
antagonist were displaced to the right and showed parallelism, but the
maximal effect was not fully reached in the presence of FR 173657. The
Schild plot (Fig 2d) had a slope (0.81) significantly different from
unity and a correlation coefficient of .99; the extrapolated
pA2 value was 9.42.
On the rabbit vascular venous (rbJV) B2 receptor, FR 173657
was effective in displacing to the right the concentration-response
curve of BK (Fig 3a). The concentration-response curves measured in the
presence of the antagonist were parallel to the control
concentration-response curve and reached the maximum (Fig 3a); the
corresponding Schild plot was linear, with a slope not significantly
different from 1.0. The pA2 value obtained by extrapolation
was 8.85 (Fig 3b).
FR 173657 acted as an antagonist also on the gpI.
Concentration-response curves of BK in this preparation were displaced
to the right but did not show parallelism; the maximal effect was
strongly depressed, especially in the presence of high concentrations
of the compound (Fig 3c). The Schild plot was linear, but its slope was
only 0.78, significantly different from unity. The extrapolated
pA2 value was 9.43 (Fig 3d).
The results obtained with FR 173657 are compared with data reported in
other articles from our group8 12 16 24 for the
B2 receptor antagonist Hoe 140 and WIN 64338 as well as
with the selective B1 receptor antagonist
Lys-[Leu8]-des-Arg9-BK. As shown in the
Table, FR 173657 was as active as Hoe 140 as an antagonist of the
B2 receptor in the human, pig, rabbit, and guinea pig. FR
173657 was inactive on the B1 receptor even in the pig, in
which high concentrations of Hoe 140 are inhibitory. In contrast, WIN
64338 acted as a potent antagonist only on the guinea pig
B2 receptor, whereas it showed low affinity on the pig and
rabbit tissues and was completely inactive on the human B2
receptor. As to Lys-[Leu8]-des-Arg9-BK, the
B1 receptor antagonist was a potent inhibitor of the
contractile responses (to Lys-des-Arg9-BK) in the human
(hUV*) and rabbit (rbA) but showed low affinity in the pig
B1 receptor (pA2, 6.7 in the pRV).
Selectivity and Specificity of Action of FR 173657
We established the selectivity of FR 173657 for the kinin
B2 receptor by showing that the compound did not affect the
contraction induced by Lys-des-Arg9-BK in the three
B1 receptor preparations (hUV*, rbA, and pRV) (Table). We
established the specificity of the antagonism exerted by FR 173657 for
the kinin B2 receptor by testing the new compound against
several agonists in the various preparations (Fig 4). At
1 µmol/L, FR 173657 did not affect (1) the contractile effects
of norepinephrine, 5-hydroxytryptamine, or endothelin-1 in the hUV°;
(2) the relaxation of the pCA in response to norepinephrine or
substance P; (3) the contractions induced by angiotensin II or
substance P in the rbJV; or (4) the myotropic effects of acetylcholine
or histamine in the gpI.
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Discussion |
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FR 173657 is the first efficient nonpeptide kinin B2 receptor antagonist reported to date.10 11 FR 173657 reduces kinin effects in vivo in the guinea pig11 and rat25 for several hours; therefore, this compound should allow evaluation of the implications of kinins and their B2 receptors in physiopathology.
In the present study, FR 173657 was found to act as an antagonist of
the B2 receptors in four species, including the human. High
affinity of FR 173657 was found in the pCA (pA2 9.4) and
gpI (pA2 9.4), and lower pA2 values were
determined in the rJV (pA2 8.9) and hUV (pA2
8.2). Such important (up to 1.2 log units) differences of affinities
among species are observed only with antagonists. In fact, the agonist
affinities in the three isolated vessels (hUV, pCA, and rbJV) are
strikingly similar, as indicated by the pEC50 values of BK
and Lys-BK in the Table. This suggests that the agonist-receptor
interactions and the transduction systems may work in a similar way in
the three vessels. On the other hand, it is well known that antagonists
discriminate better than agonists among receptor subtypes of different
species. Already, WIN 64338 has been shown to be active in the guinea
pig24 and inactive in the human,8
rabbit,24 and pig (Pruneau et al15 and
present study). Even the classic peptide B2 receptor
antagonist Hoe 140 showed differences of affinity similar to those of
FR 173657 (see comparison in the Table) between, for instance, human
(pA2 8.4) and rabbit (pA2 9.2). It therefore
appears that revealing receptor subtypes is a prerogative of
antagonists, as has already been shown in other peptide fields, for
instance, the substance P/neurokinin-1 receptor
system.26
Thus, FR 173657 appears to interact in a different way with the B2 receptors of the four species analyzed in the present study: First, FR 173657 acts as a competitive antagonist in the human and rabbit, whereas in the pig and guinea pig, it behaves as a noncompetitive antagonist. Second, FR 173657 shows apparent affinity values lower in the human and rabbit compared with the pig and guinea pig. However, it must be kept in mind that pA2 values were obtained by extrapolation from Schild plots, which in the human and rabbit had a slope near 1, whereas in the pig and guinea pig, the slope was significantly lower than 1; therefore, the extrapolated pA2 values were certainly overestimated.
FR 173657 is a pure B2 receptor antagonist that does
not interfere (up to 1 µmol/L) with human, rabbit, and pig
B1 receptors. Furthermore, this compound has no residual
agonistic activity in all species investigated (data not shown). FR
173657 is therefore a selective B2 receptor antagonist, and
its selectivity for the B2 compared with the B1
receptor may even be better than that of Hoe 140. In fact, Hoe 140 at
1 µmol/L shows some antagonistic effect on the pig
B1 receptor, whereas FR 173657 does not. Inhibitory
(relaxant) B1 receptors in the pig have been described by
Pruneau et al15 using the coronary artery of juvenile
(20-kg) animals. In the present experiment and under the same
experimental conditions, this finding could not be confirmed in
coronary artery of adult (160-kg) pigs; the different age of the
animals may explain the discrepancy between the data. We were, however,
able to demonstrate the presence of a contractile B1
receptor in the pRV. The pharmacological spectrum of the two functional
sites (B1 receptors of the pCA15 and pRV
[present study]) appears to be very similar even with respect to the
weak but consistent B1 antagonistic activity of Hoe 140
reported by Pruneau et al15 and confirmed in the present
study (see the Table).
FR 173657 is specific for the kinin B2 receptor since it does not interact with the receptors of other physiologically active peptides (substance P and angiotensin II) and amines (5-hydroxytryptamine, histamine, and acetylcholine), in accord with the data obtained by Inamura et al11 in binding assays. Moreover, the apparent affinity estimated by bioassay in the gpI (pA2 9.4) is similar to that measured by the binding in gpI plasma membrane (pIC50 9.3) by Inamura et al.11
FR 173657 is similar to Hoe 140, the classic B2 receptor antagonist, as Hoe 140 is also competitive on the human B2 receptor6 7 8 and noncompetitive in other species (rabbit and guinea pig).4 5 27 The existence of various B2 receptor subtypes related to species has been suggested to explain the findings obtained with Hoe 140 and has to be considered also to account for the different type of antagonism exerted by FR 173657.
Thus, FR 173657 appears to have all the requirements—namely, oral activity,11 long duration of action in vivo,25 high affinity, and optimal selectivity and specificity—an antagonist needs for assessment of the physiopathologic role of kinin B2 receptor and the therapeutic potentials of its inhibition. Compared with Hoe 140, FR 173657 represents real progress, especially because of its oral activity.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported by a 60% grant from the Italian Ministry of University and Scientific and Technological Research and a grant from the Medical Research Council of Canada. F.G. holds a scholarship from the Heart and Stroke Foundation of Canada. We are grateful to the personnel of the Institute of Obstetrics and Gynecology, the University of Ferrara (Italy), for their kind cooperation in collecting the umbilical cords. We would like to thank the Negrini slaughterhouse (Salara, Rovigo, Italy) for supplying the pig tissues.
Received September 3, 1996; first decision September 30, 1996; accepted October 29, 1996.
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References |
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S. Houle, J.-F. Larrivee, M. Bachvarova, J. Bouthillier, D. R. Bachvarov, and F. Marceau Antagonist-Induced Intracellular Sequestration of Rabbit Bradykinin B2 Receptor Hypertension, June 1, 2000; 35(6): 1319 - 1325. [Abstract] [Full Text] [PDF]
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F. Gobeil Jr, S. Charland, C. Filteau, S. I. Perron, W. Neugebauer, and D. Regoli Kinin B1 Receptor Antagonists Containing {alpha}-Methyl-L-Phenylalanine: In Vitro and In Vivo Antagonistic Activities Hypertension, March 1, 1999; 33(3): 823 - 829. [Abstract] [Full Text] [PDF]
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