This study proposes a new mechanism of activation of the histamine H-3-receptor based on stabilization of the active state of the receptor protein by a proton relay process. A series of histamine Hs-receptor agonists and one antagonist, all containing an imidazole and a side chain amino group, were studied using H-1 NMR and ab initio quantum mechanical calculations. A significant correlation (r = -0.87) between the formation energy of the active reaction intermediate and the agonistic activity is found. The calculated proton-transfer energies and pK(a) values of the reaction intermediates (at the MP2/6-31+G*//HF/6-31+G* level in the gas and aqueous phases), as well as, H-1 NMR conformational analysis, enable a qualitative and quantitative determination of intramolecular hydrogen bonding and its effect on proton release from the imidazole N(tau)-atom. The results indicate that the histamine H-3-receptor is not activated by a proton release from imidazole N(tau)-atom but through adoption of a folded conformation of the ligand which stabilizes the active state of the receptor by an intramolecular hydrogen bond.