Molecular determinants for the agonist activity of 2-methylhistamine and 4-methylhistamine at H2-receptors.

A model for drug action at the histamine H2-receptor has been evaluated computationally for the agonists 2- and 4-methylhistamine. Based on molecular properties calculated for molecular structures optimized with ab initio quantum mechanical methods, the activities of these compounds and their potencies relative to histamine are found to be explained by the previously proposed model. Recognized in the N3-H tautomeric form of their monocations, both compounds exhibit a change in ring tautomeric preference when the cationic side chain is neutralized. This change makes possible their participation in a proposed proton relay event that was postulated to initiate the receptor response of H2-agonists. The relative concentrations of the mono- and dication forms of the molecules in equimolar concentrations of histamine and the two derivatives are calculated from the values of the molecular electrostatic potentials at the ring protonation sites. Because the monocation is the species recognized at the H2-receptor, the reduced potency of 2-methylhistamine relative to histamine and to the 4-methyl derivative is explained by the finding that 2-methylhistamine will have the lowest concentration of the recognized species. The rank order of potencies obtained from the ratio of monocationic species of the molecules is in agreement with experimental results.