The skeletal muscle relaxer cyclobenzaprine is a potent non‐competitive histamine H1 receptor antagonist

Cyclobenzaprine (Flexeril®) is a tricyclic dimethylpropanamine skeletal muscle relaxant that is used clinically to decrease muscle spasm and hypercontractility, without altering homeostatic muscle function. Although the absolute mechanism of action of cyclobenzaprine is unknown, it acts centrally to reduce tonic somatic motor function, likely via modulation of serotonergic and/or noradrenergic systems. While cyclobenzaprine is effective as a muscle relaxant, greater than 30% of patients experience drowsiness and sedative effects, yet, the mechanisms that cause these side effects are also undescribed. Based on this common adverse effect profile and the structural similarity of cyclobenzaprine to tricyclic antidepressants, we hypothesized that cyclobenzaprine facilitates sedative effects via off‐target antagonism of central histamine H1 receptors (H1R). Here, for the first time, we present data that demonstrate that cyclobenzaprine exhibits low nanomolar affinity for the cloned human H1R, as well as that expressed in both rat and mouse brain. Using saturation binding experiments, our results demonstrate that cyclobenzaprine binds to the H1R in a non‐competitive manner. Finally, using functional Ca +2 influx assays and novel TRUPATH BRET sensors, we show that cyclobenzaprine also blocks histamine‐mediated H1R functional activity in a non‐competitive manner. Given that cyclobenzaprine readily crosses the blood‐brain barrier and its muscle relaxant effects occur centrally, our data suggest that off‐target central antagonism of H1R by cyclobenzaprine facilitate the significant sedative effect of this agent seen in patients.