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首页> 外文期刊>Life sciences >MOLECULAR PROBES FOR MUSCARINIC RECEPTORS - FUNCTIONALIZED CONGENERS OF SELECTIVE MUSCARINIC ANTAGONISTS
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MOLECULAR PROBES FOR MUSCARINIC RECEPTORS - FUNCTIONALIZED CONGENERS OF SELECTIVE MUSCARINIC ANTAGONISTS

机译：肌肉受体的分子问题-选择性肌肉拮抗剂的功能同源物

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摘要

The muscarinic agonist oxotremorine and the tricyclic muscarinic antagonists pirenzepine and telenzepine have been derivatized using a functionalized congener approach for the purpose of synthesizing high affinity ligand probes that are suitable for conjugation with prosthetic groups, for receptor cross-linking, fluorescent and radioactive detection, etc. A novel fluorescent conjugate of TAC (telenzepine amine congener), an n-decylamino derivative of the mi-selective antagonist, with the fluorescent trisulfonated pyrene dye Cascade Blue may be useful for assaying the receptor as an alternative to radiotracers. In a rat m3 receptor mutant containing a single amino acid substitution in the sixth transmembrane domain (Asn507 to Ala) the parent telenzepine lost 636-fold in affinity, while TAC lost only 27-fold. Thus, the decylamino group of TAC stabilizes the bound state and thus enhances potency by acting as a distal anchor in the receptor binding site. We have built a computer-assisted molecular model of the transmembrane regions of muscarinic receptors based on homology with the G-protein coupled receptor rhodopsin, for which a low resolution structure is known. We have coordinated the antagonist pharmacophore (tricyclic and piperazine moieties) with residues of the third and seventh helices of the rat m3 receptor. Although the decylamino chain of TAC is likely to be highly flexible and may adopt many conformations, we located one possible site for a salt bridge formation with the positively charged -NH3+ group, i.e. Asp113 in helix II. [References: 30]
机译：毒蕈碱激动剂oxotremorine和三环毒蕈碱拮抗剂pirenzepine和telenzepine已使用功能化同类方法衍生化，目的是合成适合与假体基团缀合的高亲和力配体探针，用于受体交联，荧光和放射性检测等一种新的TAC（telenzepine胺同类物）的荧光共轭物（mi-选择拮抗剂的正癸胺基衍生物）与荧光三磺化pyr染料级联蓝的结合，可用于测定受体作为放射性示踪剂的替代物。在大鼠m3受体突变体中，该突变体在第六个跨膜结构域中具有单个氨基酸取代（从Asn507到Ala），亲代Telenzepine的亲和力损失636倍，而TAC仅损失27倍。因此，TAC的癸基氨基基团通过充当受体结合位点的远侧锚而稳定了结合状态，从而增强了效力。我们基于与G蛋白偶联受体视紫红质的同源性，建立了毒蕈碱受体跨膜区的计算机辅助分子模型，已知该蛋白的低分辨率结构。我们已经将拮抗剂药效团（三环和哌嗪部分）与大鼠m3受体第三和第七个螺旋的残基进行了协调。尽管TAC的癸氨基链可能具有很高的柔性并可能采用许多构象，但我们找到了一个带正电荷的-NH3 +基团（即螺旋II中的Asp113）的盐桥形成的可能位点。 [参考：30]

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