Ab initio quantum mechanical calculations are used to explore the interaction of dimaprit, a histamine H2‐receptor agonist, with a molecular complex designed to model the specific recognition of histamine, and the H2‐receptor activation mechanism triggered by the binding of the ligand. The stabilization of several isomeric forms of the isothiourea moiety of dimaprit in the receptor model is considered, including models for the monocationic and dicationic forms that are likely to exist under physiological conditions. The energetics of proton transfer from a receptor site to the ligand are evaluated in the presence and absence of models for other sites in the receptor. The energetic contribution of ligand desolvation to the various steps in the receptor binding and activation mechanism is estimated from calculations of the enthalpy of solvation in water represented as a continuum dielectric. The results indicate that the most likely manner in which dimaprit mimics the binding of histamine to the proposed proton donor site in the H2‐receptor model requires the sulfur in the isothiourea moiety of dimaprit to act as the proton acceptor in the activation mechanism. The simulation of this mechanism reveals its feasibility and indicates that the monocation form of dimaprit, rather than the dication, is likely to be the physiologically active species.