G-protein-coupled receptors (GPCRs) mediate the effects of approximately 33% of all marketed drugs. The development of tools to study GPCR pharmacology is urgently needed as it can lead to the discovery of safer and more effective medications. Fluorescent GPCR ligands represent highly sensitive and safe small-molecule tools for real-time exploration of the life of the receptor, cellular signaling, and ligand-/receptor-receptor interactions in cellulo and/or in vivo. Areas covered: This review summarizes relevant information from published literature and provides critical insights into the design of successful small-molecule fluorescent probes for Class A GPCRs as potential major targets for drug development. Expert opinion: Considering the rapid progress of fluorescence technologies, effective small-molecule fluorescent probes represent valuable pharmacological tools for studying GPCRs. However, the design and development of such probes are challenging, largely due to the low affinity/specificity of the probe for its target, inadequate photophysical properties, extensive non-specific binding, and/or low signal-to-noise ratio. Generally speaking, fluorescent and luminescent small-molecule probes, receptors, and G proteins in combination with FRET and BRET technologies hold great promise for studying kinetic profiles of GPCR signaling.
Keywords: Fluorescent probes; G-protein coupled receptors; drug development; imaging.