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 was evaluated computationally for the agonists 2- and 4-methylhistamine. On the basis of mol. properties calcd. for mol. structures optimized with ab initio quantum mech. methods, the activities of these compds. and their potencies relative to histamine are explained by the previously proposed model. Recognized in the N3-H tautomeric form of their monocations, both compds. 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 concns. of histamine and the 2 derivs. are calcd. from the values of the mol. 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-Me deriv. is explained by the finding that 2-methylhistamine will have the lowest concn. of the recognized species. The rank order of potencies obtained from the ratio of monocationic species of the mols. is in agreement with exptl. results