ISSN:
1432-1912
Schlagwort(e):
Rat reticulocytes
;
Beta-adrenoreceptors
;
Apparent irreversible ligand
;
Carbostyril derivatives
Quelle:
Springer Online Journal Archives 1860-2000
Thema:
Medizin
Notizen:
Summary The interaction of the carbostyril derivatives 5-[2-[[1-(4-aminophenyl)-2-methyl-prop-2-yl]amino]-1-hydroxyethyl]-8-hydroxycarbostyril (carbo-amine) and 5-[2[[3-[4-(bromoacetamido)phenyl]-2-methylprop-2-yl]amino]1-hydroxyethyl]-8-hydroxycarbostryril (carbo-Br) with the rat reticulocyte beta-adrenoreceptor system has been partially characterized. In the absence of a guanine nucleotide, the concentration of carbo-amine, carbo-Br and (−)isoprenaline that inhibited (−)-[125I]iodocyanopindolol ([125I]CYP) binding by 50% (IC50) was 5.9 ± 0.2, 3.3 ± 0.3 and 49 ± 3 nM, respectively. In the presence of a guanine nucleotide, the (IC50) values were carbo-amine, 21 ± 0.6 nM; carbo-Br, 7.6 ± 0.3 nM and (−)isoprenaline, 813 ± 66 nM. Preincubation of membranes with either of the carbostyril congeners followed by washing reduced specific [125I]CYP binding capacity without changing the K D value for the remaining receptors. The beta-antagonist nadolol largely prevented the receptor reduction induced by the carbostyril compounds. Incubation of membranes for 18 It at 25°C resulted in an 11 % recovery of the carbo-amine-induced receptor loss and no recovery of the receptors lost by preincubation with carbo-Br. However, the carbo-amine induced receptor loss could be largely reversed (80%) by membrane heating at 45°C whereas little reversal (〈 10%) was observed with the carbo-Br pretreated membranes. The concentration of carbo-amine, carbo-Br and (−)isoprenaline that stimulated halt-maximal cAMP formation in reticulocyte membranes was 17.8 ± 3.1, 8.2 ± 2.1 and 241 ± 17 nM, respectively, and all 3 agonists produced the same maximal response. Initial cAMP formation stimulated by the carbostyril derivatives and (−)isoprenaline was blocked by concurrent addition of propranolol. However, the addition of propranolol after 7 min of incubation with either of the two carbostyril derivatives did not affect further cAMP production whereas with (−)isoprenaline further cAMP production was blocked. The data indicate that both carbostyril-derivatives are potent, full beta-adrenoreceptor agonists and the carbo-amine bound to the beta-adrenoreceptor in a tight, slowly dissociating manner whereas carbo-Br binding shows an apparent irreversible interaction with the receptor.
Materialart:
Digitale Medien
URL:
http://dx.doi.org/10.1007/BF00165134
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