Biochemical characterization of the antagonist actions of the xanthines, PACPX (1,3-dipropyl-8(2-amino-4-chloro)phenylxanthine) and 8-PT (8-phenyltheophylline) at adenosine A1 and A2 receptors in rat brain tissue
1987; Elsevier BV; Volume: 36; Issue: 22 Linguagem: Inglês
10.1016/0006-2952(87)90476-x
ISSN1873-2968
AutoresMichael Williams, Michael F. Jarvis, Matthew A. Sills, John W. Ferkany, Albert Braunwalder,
Tópico(s)Receptor Mechanisms and Signaling
Resumo8-(3,4-Dimethoxystyryl)-1,3-dipropyl-7-methylxanthine exhibited high affinity and selectivity for adenosine A2A receptors in binding assay using rat striatal A2A receptors labeled with [3H2-[p-(2-carboxyethyl)-phenethylamino]-5′-N-ethylcarboxamido- adenosine (CGS21680). The affinity was stereo selective: the E isomer, KF17837, showed a Ki value of 1.0 ±0.057 nM for the A2A receptors, whereas the Z isomer showed much lower affinity. KF17837 had 62-fold selectivity for the A2A receptors versus rat forebrain A1 receptors labeled with [3H]N6-cyclohexyladenosine (CHA). KF17837 was rapidly photoisomerized to form a stable equilibrium mixture (18% E − 82% Z), KF17837S, which showed Ki values of 7.9 ± 0.055 nM and 390 ± 68 nM for the A2A and A1 receptors, respectively. The inhibition type was competitive for [3H]CGS21680 binding. In rat pheochromocytoma PC12 cells KF17837S antagonized cAMP accumulation induced by 1 μM CGS21680 via the A2A receptors, with an IC50 value of 53 ± 10 nM. cAMP accumulation induced by 10 μM 5′-N-ethylcarboxamidoadenosine via the A2B receptors in Jurkat cells (human T-cell line) was inhibited by KF17837S with an IC50 value of 1500 ± 290 nM. These results indicate that KF17837S (and hence KF17837) is a highly potent and selective adenosine A2A receptor antagonist.
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