1-(2,6-二甲氧基)-2-(3,4-二甲基苯乙氨基)丙烷盐酸盐(DDPH)拮抗α1肾上腺素受体的特性

目的　研究DDPH对α₁-肾上腺素受体(α₁-AR)及其亚型的拮抗作用。方法　放射配体结合实验和离体血管收缩功能实验。结果　DDPH对¹²⁵I-BE2254与大鼠脑皮质和脾脏α₁-AR结合呈竞争性拮抗作用。pK_I值在两者间无显著性差别, Hill系数均接近于1.0。在分别稳定表达α_1A，α_1B或α_1D-AR的克隆HEK293细胞中，其拮抗的pK_I值α_1A和α_1D比α_1B-AR高约2倍，Hill系数均接近于1.0。并拮抗去甲肾上腺素(NE)介导大鼠主动脉,肾动脉和脾脏收缩的pA₂值，在三者间无显著差别，斜率接近1.0。结论　DDPH对α₁-AR有竞争性拮抗作用，但其作用对α₁-AR亚型无选择性。

Antagonistic characterization of 1-(2,6-dimethylphenoxyl)-2-(3,4-dimethylphenyl ethylamino) propane hydrochloride on alpha 1-adrenoceptor]

AIM: To study the antagonistic effect of 1-(2,6-dimethylphenox)-2-(3,4-dimethylphenyl ethylamino) propane hydrochloride (DDPH) on alpha 1-adrenoceptor (AR). METHODS: Radioligand binding assay was used. Specific 125I-BE2254 (2-beta(4-hydroxyphenyl)-ethyl aminomethyl-tetralone) binding was measured by incubating membrane of rat cerebral cortex, spleen and the three cloned alpha 1-AR subtypes (alpha 1A, alpha 1B, alpha 1D) stably expressed in human embryonic kidney 293 cell preparation with a single concentration of 125I-BE2254 in the presence of 14 concentrations of DDPH. Equilibrium binding constant (KI) and Hill coefficients (nH) were determined from Hill plots. The -log value of the KI was expressed as pKI. Contractile responses of isolated rat aorta, renal artery ring and spleen were determined. The pA2 values for DDPH in competitively inhibiting NE-stimulated contraction of tissues were measured with the method of Ainlakshana and Schild. RESULTS: DDPH competitively inhibited binding of 125I-BE2254 to alpha 1-AR in a concentration-dependent manner. The pKI values for DDPH in rat cerebral cortex and spleen were 7.17 +/- 0.06 and 7.41 +/- 0.11, respectively, and the Hill efficiency values were not significantly different from unit. The pKI values for cloned alpha 1A, alpha 1B and alpha 1D-AR were 7.21 +/- 0.12, 6.88 +/- 0.04 and 7.26 +/- 0.06, respectively, and the Hill efficiency values were not significantly different from unit. Contractile studies showed that DDPH competitively antagonized the NE concentration-response curve with a pA2 values of 7.40 +/- 0.23 in aorta, 7.41 +/- 0.04 in renal artery and 7.63 +/- 0.07 in spleen and the slopes of schild plot were not significantly different from unit. The pKI values for DDPH in tissues and the cloned alpha 1A or alpha 1D-AR were shown to fit well in with the pA2 values in antagonizing NE-induced constriction in rat isolated aorta, renal artery and spleen. CONCLUSION: These results suggest that DDPH appear to be a non-subtype selective competitive antagonist for alpha 1-AR.