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immediately placed in Krebs’ solution of the following composition:
119 mM NaCl, 4.7 mM KCl, 1.5 mM MgSO4, 2.5 mM CaCl2, 1.2 mM
KH2PO4, 25 mM NaHCO3, 5.5 mM glucose, and 0.026 mM EDTA.
The fundus was dissected free, and segments were suspended under a
resting tension of 1 g in 8 mL jacketed organ baths containing Krebs’
solution maintained at 37 °C and bubbled with 95% O2 and 5% CO2.
After a 4 h resting period, the maximal contraction was measured in
each segment by adding carbachol (10 μM). After the samples were
washed twice with Krebs’ solution and returned to baseline, captopril
(10 μM), DL-thiorphan (1 μM), mepyramine (1 μM), and
indomethacin (3 μM) were added to the organ bath. After 30 min,
vehicle or compound was applied to the organ bath. This mixture was
incubated for 30 min, and concentration−response curves to des-
Arg10-kallidin were obtained. Each segment was used for a single
concentration−response curve. The contractile responses to des-
Arg10-kallidin were expressed as a percentage of the maximal
contraction to carbachol.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Synthetic procedures for all intermediates 5a, 6f,g, 7a−c,e−g,
8a−c,e−g, 9a−c,e−h, 10a−c,e−g, 12a−c,e−m,o−r, 20b−h,
21b−h, and 23−26. This material is available free of charge via
AUTHOR INFORMATION
Corresponding Author
■
Notes
The authors declare no competing financial interest.
ABBREVIATIONS USED
■
ADME, absorption, distribution, metabolism, and excretion;
BK, bradykinin; COS, monkey kidney fibroblast cells; CYP,
cytochrome P450; EDCI, 1-ethyl-3-(3-dimethylaminopropyl)-
carbodiimide; HEK293, human endothelium kidney 293;
HOAT, 1-hydroxy-7-azabenzotriazole; PSA, polar surface
area; SAR, structure−activity relationship; TM, transmembrane
spanning domain
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