Ab initio study of the molecular activation mechanism of the histamine H2-receptor

Abstract

The ability of imidazole and triazole agonists to be recognized at the histamine H2-receptor and to activate it is evaluated by simulating the events leading to the biological response by means of ab initio quantum chemical methods. Results reveal a shift in the tautomeric preference upon deprotonation (or neutralization). The neutralization of the monocationic agonist changes the proton affinities of the heterocycle ring nitrogens. Such change triggers the proton relay system. A quantitative description of the H2-agonist potency is provided by the energetics of both sequential proton transfer processes. The relevance of other factors, such as affinity, in modulating the agonist activity is discussed.