New activation model for the histamine H2 receptor, explaining the activity of the different classes of histamine H2 receptor agonists.

Recently we developed amthamine [2-amino-5-(2-aminoethyl)-4-methylthiazole]. This cyclic analogue of dimaprit proved to be the most potent and selective histamine H2 receptor agonist of a series of substituted 4- or 5-(2-aminoethyl)thiazoles. Quantum chemical studies on histamine (N pi-H tautomer), dimaprit, and amthamine revealed that, based upon geometries of molecular electrostatic potentials, it is likely that these agonists accept a proton from the proton-donating receptor site on their double-bonded (heteroaromatic) nitrogen atoms. In contrast to reported models, this new model is able to accommodate and explain the agonistic activities of all known (including nontautomeric) histamine H2 receptor agonists. Quantitative structure-activity relationship studies with a series of substituted histamine derivatives and heterocyclic analogues support the presented model, in which the monocations in extended conformation interact with the receptor surface; their affinities correlate with the proton association constants of the heteroaromatic nuclei. The negatively charged anchoring site for the ethylammonium side chain of these agonists in this model is a functional group with a pKa value of 4.17.