Monoamine neurotransmitters such as serotonin, dopamine, histamine, and noradrenaline have important and varied physiological functions and similar chemical structures. Representing important pharmaceutical drug targets, the corresponding G-protein-coupled receptors (termed aminergic GPCRs) belong to the class of cell membrane receptors and share many levels of similarity as well. Given their pharmacological and structural closeness, one could hypothesize the possibility to derivatize a ubiquitous ligand to afford rapidly fluorescent probes for a large set of GPCRs to be used for instance in FRET-based binding assays. Here we report fluorescent derivatives of the nonselective agent asenapine which were designed, synthesized, and evaluated as ligands of 34 serotonin, dopamine, histamine, melatonin, acetylcholine, and adrenergic receptors. It appears that this strategy led rapidly to the discovery and development of nanomolar affinity fluorescent probes for 14 aminergic GPCRs. Selected probes were tested in competition binding assays with unlabeled competitors in order to demonstrate their suitability for drug discovery purposes.

中文翻译：

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从混杂的阿塞那平到有力的荧光配体，作用于一系列与矿质G蛋白偶联的受体

单胺神经递质（例如5-羟色胺，多巴胺，组胺和去甲肾上腺素）具有重要且变化的生理功能和相似的化学结构。代表重要的药物靶标，相应的G蛋白偶联受体（称为胺能GPCR）属于细胞膜受体，并且也具有许多相似度。考虑到它们的药理和结构紧密性，可以假设有可能衍生出一个普遍存在的配体，以提供用于大量GPCR的快速荧光探针，这些GPCR例如用于基于FRET的结合测定中。在这里，我们报告非选择性药物阿塞那平的荧光衍生物，这些衍生物被设计，合成和评估为34种血清素，多巴胺，组胺，褪黑激素，乙酰胆碱和肾上腺素能受体的配体。看来，这种策略迅速导致了针对14种胺能GPCR的纳摩尔亲和力荧光探针的发现和开发。为了证明所选探针适合用于药物发现目的，在竞争结合测定中与未标记的竞争者进行了测试。