Small-molecule fluorescent probes for the aminergic GPCRs – What new tool compounds do we have post-2014 and what can they do?

Aminergic G protein-coupled receptors (GPCRs) are heavily involved in the physiological functions of the human body and represent prominent drug targets for numerous diseases. Despite extensive work over the years, knowledge gaps persist as not all aminergic GPCRs are currently drugged. This gap could be addressed by using small-molecule fluorescent probes across a range of assay formats and experiments to obtain deeper insights into the molecular pharmacology of these receptors. This review highlights key developments from 2014 to 2024 in the design and application of fluorescent probes targeting aminergic GPCRs, featuring a total of 36 fluorescent probes spanning all prominent aminergic GPCR subfamilies: adrenergic, dopaminergic, histaminergic, muscarinic, and serotonergic receptors. This review provides a detailed overview of the approaches to probe design, their pharmacological profiles and their reported utilities in ligand binding assays and imaging studies. In recent years, these applications have expanded to include ex vivo and in vivo studies in both mice and human tissue models. With the integration of cutting-edge image processing and artificial intelligence-driven image recognition technologies, fluorescent probes will remain indispensable tools for investigating the molecular pharmacology of aminergic GPCRs, playing a crucial role in driving forward drug discovery in this field.