α2-adrenoceptor antagonist and 5-HT uptake inhibitor
A-80426 is a potent and selective α2-adrenoceptor antagonist, it can block serotonin uptake and have putative antidepressant-like effects. It inhibits synaptosomal serotonin (5HT) uptake with an IC50 value of 13 nM and blocks [3H]-paroxetine binding to 5HT uptake sites with a Ki value of 3.8 nM. It inhibits [3H]-rauwolscine binding to α2-adrenoceptors with a Ki value of 2.0 nM, and blocks α2-adrenoceptors with a pEC30 of 7.4-7.5 in electrically stimulated rat vas deferens and atria [1].
α2-adrenoceptors mediate many physiological actions of endogenous noradrenaline and catecholamines adrenaline [2].
In radioligand binding assays with isolated tissues, the potent blocking activity of A-80426 against α2-adrenoceptor is not reflected [1].
P-chloroamphetamine (PCA)-induced hyperactivity is a measure of the blockade of serotonin uptake in vivo. In rats, p-chloroamphetamine (PCA)-induced hyperactivity was significantly reduced by A-80426 at doses of chronic (14 days) (ED50=4.1 ?mol/kg, po) and acute (ED50= 13 ?mol/kg, po). Administration (po) of A-80426 at doses of 6.7 and 22?mol/kg was effective for at least 12 h. Doses of 6.7 to 224?mol/kg, ip, of A-80426 failed to block hypoactivity and hypothermia resulted from the administration of α2-adrenoceptor agonist clonidine. Doses of 100 and 300 ?mol/kg, po, were required to block the mydriasis induced by clonidine [3].
参考文献:
[1].? Hancock AA, Buckner SA, Oheim KW, et al. A-80426, a potent α2-adrenoceptor antagonist with serotonin uptake blocking activity and putative antidepressant-like effects: I. Biochemical profile. Drug Development Research, 1995, 35(4): 237-245.
[2].? Aantaa R, Marjam?ki A and Scheinin M. Molecular Pharmacology of α2-adrenoceptor Subtypes. Annals of Medicine, 1995, 27(4): 439-449.
[3].? Giardina WJ, Buckner SA, Brune ME, et al. A-80426, A Potent and Selective α2-Adrenoceptor Antagonist With Serotonin Uptake-Blocking Activity and Putative Antidepressant-Like Effects: II. Pharmacology Profile. Drug Development Research, 1995, 35(4): 246-260.
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