一种新的α1A肾上腺素受体选择性拮抗剂—Sertindole

本工作分别在稳定表达α_1A,α_1B和α_1D肾上腺素受体(adrenoceptor,AR)的人胚胎肾脏细胞( human embryonic kidney 293,HEK 293)和大鼠离体血管上,用放射配体结合实验和离体血管收缩功能实验方法以确定sertindole对α₁-AR亚型的选择性拮抗作用。结果显示sertindole与克隆α_1A-AR的亲和性分别是与克隆α_1B-AR和克隆α_1D-AR的69倍和132倍。Sertindole拮抗去甲肾上腺素引起的主动脉和肾动脉收缩反应的pA₂值分别与其对α_1D和α_1A亚型的pKI值相符。分别稳定表达3种亚型受体的HEK293细胞膜标本经与sertindole预温育30min后,受体与¹²⁵IBE2254结合的B_max值显著降低,KD值无显著变化;而在 sertindole 存在条件下,α₁-AR3种亚型与¹²⁵IBE2254 结合的KD值显著增大,但B_max值无显著改变。上述结果表明sertindole为不可逆性竞争性α₁-AR拮抗剂,并有α_1A亚型选择性。

Sertindole, a novel alpha 1A-adrenoceptor selective antagonist]

The antagonism effect of sertindole on alpha 1-AR subtypes was studied by combining radiologand binding assays in three cloned alpha 1-AR subtypes stably expressed in human embryonic kidney 293 cells and contractile response experiment in isolated rat blood vessels. The results showed that the affinity for sertindole in the cloned alpha 1A-AR (pKI 8.90 +/- 0.17) was 69-fold (pKI 7.06 +/- 0.09) and 132-fold (pKI 6.78 +/- 0.07) higher than that for the cloned alpha 1B- and alpha 1D-AR, respectively. The pA2 values for sertindole in antagonizing NE-induced vasoconstriction in isolated rat aorta and renal artery were shown to fit well to the pKI values on cloned alpha 1D- and alpha 1A-AR, respectively. Pretreatment of membrane preparations with sertindole for 30 min significantly reduced the maximal binding capacities. (Bmax) of 125 IBE2254 to the three cloned alpha 1-AR subtypes without alteration of affinities (KD values). In the presence of sertindole, the Bmax of 125IBE2254 binding to the cloned alpha 1-ARs were not significantly changed, while the KD values were significantly increased. Thus, sertindole is a selective irreversible competitive alpha 1-AR antagonist with alpha 1A subtype.