Synthesis and characterization of arylamine derivatives of rauwolscine as molecular probes for alpha 2-adrenergic receptors.
Synthesis and characterization of arylamine derivatives of rauwolscine as molecular probes for alpha 2-adrenergic receptors.
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作为 α2-肾上腺素能受体分子探针的萝芙素芳胺衍生物的合成和表征。
DOI：
10.1161/01.hyp.9.6_pt_2.iii120
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发表时间：
1987
期刊：
影响因子：
--
通讯作者：
Homcy,CJ
中科院分区：
文献类型：
--
作者：
Lanier,SM;Graham,RM;Hess,HJ;Grodski,A;Repaske,MG;Nunnari,JM;Limbird,LE;Homcy,CJ
对α 2-肾上腺素能受体拮抗剂萝芙木碱进行了结构修饰，得到了一系列芳胺酰胺衍生物，并将其作为α 2-肾上腺素能受体定位和结构表征的潜在分子探针。芳胺甲酰胺的不同之处在于将反应性苯基部分与母体化合物萝芙木碱羧酸酯的稠环结构分开的碳原子数。大鼠肾膜中[3 H]萝芙木碱的竞争性抑制研究表明，对羧酰胺衍生物的亲和力与碳间隔臂的长度呈负相关，萝芙木碱4-氨基苯基羧酰胺（零碳间隔臂; rau-AMPC）表现出最高亲和力（Kd = 2.3 +/- 0.2 nM）。rau-AMPC的放射性碘化产生配体125 I-rau-AMPC，其以高亲和力与大鼠肾脏α 2-肾上腺素能受体结合，这通过动力学分析（Kd = k2/k1 = 0.016 min-1/2.1 X 10（7）M-1 min-1 = 0.76 nM）和平衡结合研究（Kd = 0.78 +/- 0.16 nM）确定。125 I-rau-AMPC定量转化为光不稳定的芳基叠氮化物衍生物17 α-羟基-20 α-育亨班-16 β-（N-4-叠氮基-3-[125 I]碘苯基）甲酰胺（125 I-rau-AZPC）。在猪脑的部分纯化的受体制剂中，该化合物光标记主要（Mr = 62，000）肽。该肽的标记被肾上腺素能激动剂和拮抗剂抑制，其效力等级顺序与α 2-肾上腺素能受体结合位点一致。125 I-rau-AMPC和光不稳定的芳基叠氮化物衍生物125 I-rau-AZPC，应证明是有用的分子探针的结构和生化特性的α 2-肾上腺素能受体。
The selective alpha 2-adrenergic receptor antagonist rauwolscine was structurally modified to yield a series of arylamine carboxamide derivatives, which were investigated as potential molecular probes for the localization and structural characterization of alpha 2-adrenergic receptors. The arylamine carboxamides differ in the number of carbon atoms separating the reactive phenyl moiety from the fused ring structure of the parent compound, rauwolscine carboxylate. Competitive inhibition studies with [3H]rauwolscine in rat kidney membranes indicate that the affinity for the carboxamide derivatives is inversely related to the length of the carbon spacer arm with rauwolscine 4-aminophenyl carboxamide (zero carbon spacer arm; rau-AMPC) exhibiting the highest affinity (Kd = 2.3 +/- 0.2 nM). Radioiodination of rau-AMPC yields a ligand, 125I-rau-AMPC, which binds to rat kidney alpha 2-adrenergic receptors with high affinity, as determined by both kinetic analysis (Kd = k2/k1 = 0.016 min-1/2.1 X 10(7) M-1 min-1 = 0.76 nM) and equilibrium binding studies (Kd = 0.78 +/- 0.16 nM). 125I-rau-AMPC was quantitatively converted to the photolabile arylazide derivative 17 alpha-hydroxy-20 alpha-yohimban-16 beta-(N-4-azido-3-[125I]iodophenyl) carboxamide (125I-rau-AZPC). In a partially purified receptor preparation from porcine brain, this compound photolabels a major (Mr = 62,000) peptide. The labeling of this peptide is inhibited by adrenergic agonists and antagonists with a rank order of potency consistent with an alpha 2-adrenergic receptor binding site. Both 125I-rau-AMPC and the photolabile arylazide derivative, 125I-rau-AZPC, should prove useful as molecular probes for the structural and biochemical characterization of alpha 2-adrenergic receptors.