Cyclobenzaprine Hydrochloride

Cyclobenzaprine hydrochloride is a centrally acting skeletal muscle relaxant structurally related to tricyclic antidepressants and first-generation antihistamines. Radioligand binding assays using [³H]-mepyramine demonstrated that cyclobenzaprine exhibits high affinity for the cloned human histamine H1 receptor and for H1 receptors expressed in rat and mouse brain, with low nanomolar affinity. Saturation binding analysis revealed that cyclobenzaprine binds to the H1 receptor in a noncompetitive manner, distinct from the competitive binding of classical H1 antagonists such as diphenhydramine. Functional assays measuring calcium influx and G-protein subunit activation via BRET biosensors confirmed that cyclobenzaprine blocks histamine-mediated H1 receptor functional activity through a noncompetitive mechanism. This H1 receptor antagonism occurs at clinically relevant concentrations and likely contributes to the significant sedative effects observed in patients taking cyclobenzaprine, as the drug readily crosses the blood-brain barrier.

Fig. 1 Antagonism of histamine H1 receptors by Cyclobenzaprine. (Singh K.; et al. 2022)