Bibliothek

feed icon rss

Ihre E-Mail wurde erfolgreich gesendet. Bitte prüfen Sie Ihren Maileingang.

Leider ist ein Fehler beim E-Mail-Versand aufgetreten. Bitte versuchen Sie es erneut.

Vorgang fortführen?

Exportieren
  • 1
    ISSN: 1432-2013
    Schlagwort(e): Cl−-channel blocker ; Thick ascending limb of the loop of Henle ; Diphenylamine-2-carboxylate ; Cl−-channel
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Abstract On the basis of our findings with diphenylamine-2-carboxylate [5] we have searched for compounds which possess an even higher affinity for the Cl−-channels in the basolateral membrane of the thick ascending limb of the loop of Henle. To quantitiy the inhibitory potency, we performed measurements of the equivalent short circuit current, corresponding to the secondary active transport of Cl− [8] and measurements of the voltage across the basolateral membrane. A survey of 219 compounds reveals that relatively simple modifications in the structure of diphenylamine-2-carboxylate led to very potent blockers such as 5-nitro-2-(3-phenylpropylamino)-benzoate which inhibits the short circuit current half maximally (IC50) at 8·10−8 mol/l. A comparison of the structural formula and the respective IC50 values leads to several empirical conclusions: 1. The potent compounds are lipophilic due to the apolar residue (e.g. phenyl- or cycloalkyl group). Replacing this part of the molecule by an aliphatic chain (up to 4 C-atoms) leads to inactive compounds. 2. Most of the inhibitors are secondary amines. Linking other than with-NH- between the phenyl ring and the benzoic acid results in inactive compounds. Tertiary amines, such as in case of 2-(N,N-diphenylamine) benzoic acid or N-methylphenylaminebenzoic acid are poorly active. 3. The carboxylate group of the benzoate moiety must be in ortho position to the amino group. 4. Introduction of substituents into the benzoate moiety e.g.-NO2 (in meta position to the carboxylate group), or by-Cl (in para position to the carboxylate group) results in an increase of inhibitory potency. 5. A-CH2-,-C2H4-,-C3H6-) spacer between the amino bridge and the phenyl ring increases the affinity for the Cl−-channel by several orders of magnitude. The above described structure activity relationship renders it likely that these chloride channel blockers possess several sites of interaction: The negatively charged carboxylate group, the secondary amine group which probably carries a positive partial charge, and for the very potent agents (nos. 130, 143, 144, and 145) an additional negative partial charge at the respective-Cl or-NO2 substituent. Finally, also an apolar interaction with an cycloalkyl or cycloaryl residue seems to be required, and this site of interaction has a defined spacing from the secondary amino nitrogen.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
    BibTip Andere fanden auch interessant ...
  • 2
    Digitale Medien
    Digitale Medien
    Springer
    The journal of membrane biology 147 (1995), S. 255-262 
    ISSN: 1432-1424
    Schlagwort(e): Labyrinth ; Slowly activating K+ channel ; IsK channel ; MinK channel ; pH
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Biologie , Chemie und Pharmazie
    Notizen: Abstract The pH-sensitivity of transepithelial K+ transport was studied in vitro in isolated vestibular dark cell epithelium from the gerbil ampulla. The cytosolic pH (pH iwas measured microfluorometrically with the pH-sensitive dye 2′,7′-bicarboxyethyl-5(6)-carboxyfluorescein (BCECF) and the equivalent short-circuit current (I sc), which is a measure for transepithelial K+ secretion, was calculated from measurements of the transepithelial voltage (V t)and the transepithelial resistance (R t) in a micro-Ussing chamber. All experiments were conducted in virtually HCO 3 − -free solutions. Under control conditions, pH iwas 7.01±0.04 (n=18), V twas 9.1±0.5 mV, R t16.7±0.09 Ωcm2, and I sc was 587±30 μA/cm2 (n=49). Addition of 20 mm propionate− caused a biphasic effect involving an initial acidification of pH i, increase in V tand I sc and decrease in R tand a subsequent alkalinization of pH i, decrease of V tand increase of R t. Removal of propionate− caused a transient effect involving an alkalinization of pH i, a decrease of V tand I sc and an increase in R t. pH iin the presence of propionate− exceeded pH iunder control conditions. Effects of propionate − on V t, R tand I sc were significantly larger when propionate− was applied to the basolateral side rather than to the apical side of the epithelium. The pH i-sensitivityof I sc between pH 6.8 and 7.5 was −1089 μA/(cm2 · pH-unit) suggesting that K+ secretion ceases at about pH i7.6. Acidification of the extracellular pH (pH o)caused an increase of V tand I sc and a decrease of R tmost likely due to acidification of pH i. Effects were significantly larger when the extracellular acidification was applied to the basolateral side rather than to the apical side of the epithelium. The pH osensitivity of I sc between pH 7.4 and 6.4 was −155 μA/(cm2 · pH unit). These results demonstrate that transepithelial K+ transport is sensitive to pH iand pH oand that vestibular dark cells contain propionate− uptake mechanism. Further, the data suggest that cytosolic acidification activates and that cytosolic alkalinization inactivates the slowly activating K+ channel (I sK)in the apical membrane. Whether the effect of pH ion the I sK channel is a direct or indirect effect remains to be determined.
    Materialart: Digitale Medien
    Bibliothek Standort Signatur Band/Heft/Jahr Verfügbarkeit
    BibTip Andere fanden auch interessant ...
Schließen ⊗
Diese Webseite nutzt Cookies und das Analyse-Tool Matomo. Weitere Informationen finden Sie hier...