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8-(3-Isothiocyanatostyryl)caffeine is a selective, irreversible inhibitor of striatal A2-adenosine receptors

Artículo

Autoría
GALLO, CAROLA
Fecha
1993
Editorial y Lugar de Edición
WILEY-LISS, DIV JOHN WILEY & SONS INC
Revista
DRUG DEVELOPMENT RESEARCH, vol. 29 (pp. 292-298) WILEY-LISS, DIV JOHN WILEY & SONS INC
Resumen Información suministrada por el agente en SIGEVA
8-(3-Isothiocyanatostyryl)caffeine (ISC) was synthesized and shown to inhibit selectively the binding of [3H]CGS 21680 (an A2a-selective agonist) at adenosine receptors in striatal membranes. The Ki value at A2a-receptors was found to be 110 nM (rat), with selectivity ratios for A2a versus A1-receptors in rat, guinea pig, bovine, and rabbit striatum of >100-fold. Preincubation of membranes with ISC caused a dose-dependent, irreversible antagonism of the binding of [3H]CGS 21680, with an IC50... 8-(3-Isothiocyanatostyryl)caffeine (ISC) was synthesized and shown to inhibit selectively the binding of [3H]CGS 21680 (an A2a-selective agonist) at adenosine receptors in striatal membranes. The Ki value at A2a-receptors was found to be 110 nM (rat), with selectivity ratios for A2a versus A1-receptors in rat, guinea pig, bovine, and rabbit striatum of >100-fold. Preincubation of membranes with ISC caused a dose-dependent, irreversible antagonism of the binding of [3H]CGS 21680, with an IC50 value of 3 μM. The irreversibility is likely due to the presence of the chemically reactive isothiocyanate group, since the binding of the corresponding analogue in which the isothiocyanate was replaced with a chloro group was completely reversible. The potency of ISC to irreversibly inhibit the binding of [3H]CGS 21680 in several species varied in the order rat ≈ guinea pig > bovine ≈ rabbit. In all four species, binding of the A1-selective agonist [3H]R-N6-phenylisopropyladenosine was not diminished by pre-treatment with 2 μM ISC. The kinetics of irreversible inhibition of rat A2a-receptors by 2 μM ISC gave a t1/2 of approximately 3 min. Following partial inactivation, the remaining rat A2a-binding sites retained the same Kd value as in control membranes for saturatin by [3H]CGS 21680. Thus, ISC appears to be a selective affinity label for A2a- versus A1-receptors in the brain.
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Palabras Clave
radioligand bindingadenosine receptorsaffinity labelxanthines