Potential Mechanisms of N-Methyltyramine in Multitarget Regulation of Mental Disorders via the GPCR-cAMP Pathway.

N-Methyltyramine (NMT) is a tyramine derivative widely distributed in citrus plants and the traditional Chinese medicine Zhishi. Pharmacological studies have confirmed that NMT directly binds to the dopamine D₂ receptor (DRD2; Ki = 31.3µM), inhibits forskolin-induced cAMP accumulation (EC₅₀ ≈ 4µM, Emax = 89%), and dose-dependently antagonizes quinpirole-mediated β-arrestin2 recruitment, exhibiting G protein-biased agonistic properties. Meanwhile, NMT activates the human trace amine-associated receptor 1 (hTAAR1; EC₅₀ ≈ 2µM) to increase cAMP, possesses α₂-adrenergic receptor antagonistic activity (IC₅₀ = 5.53µM), and exhibits blood-brain barrier permeability (logPe = -5.16cm/s). Based on these multi-target receptor profiles, NMT may participate in the regulation of central monoaminergic neurotransmission via the GPCR-cAMP signaling axis, providing a new multi-target lead compound direction for research on neurological disorders such as Alzheimer's disease, depression, and drug addiction. Notably, evidence for direct activation of β₂-adrenergic receptors by NMT remains insufficient, and its therapeutic effects and downstream signal integration mechanisms require NMT-specific experimental validation.