G-protein-coupled receptors (GPCRs) are one of the largest families of cell surface proteins in the human body that recognize hormones, neurotransmitters, and drugs. These receptors regulate a wide range of physiological processes and are the targets of more than 30% of currently marketed drugs. The histamine H1 receptor (H1R) is one such GPCR subtype that plays a key role in mediating allergic reactions, inflammation, vascular permeability, airway constriction, wakefulness, and cognitive functions in the human body. While antihistamines primarily target H1R, current drugs can exhibit limited therapeutic efficacy, prompting researchers to look at H1R ligands from new perspectives.