L-Phenylalanine and Tryptophan, as direct ligands, bind to GPR139 and activate it, initiating a cascade of intracellular signaling. In contrast, compounds like Forskolin and Isoproterenol exert their effects indirectly by modulating secondary messenger systems like cAMP, which in turn can influence GPR139 activity. Calcium gluconate and Nifedipine affect GPR139 function by altering calcium signaling, a crucial factor in GPCR dynamics.Inhibitors like Genistein and G15 demonstrate the intricate interplay of kinase pathways and G-protein signaling in modulating GPR139 activity. Similarly, Dextromethorphan and Propranolol, through their respective receptor targets, can exert downstream effects on GPR139 signaling. Diazoxide, by modulating potassium channels, highlights the role of cellular excitability in GPCR function.