NEW ACTIVATION MODEL FOR THE HISTAMINE-H(2) RECEPTOR, EXPLAINING THE ACTIVITY OF THE DIFFERENT CLASSES OF HISTAMINE-H(2) RECEPTOR AGONISTS

Recently we developed amthamine [2-amino-5-(2-aminoethyl)-4-methylthia zole]. This cyclic analogue of dimaprit proved to be the most potent a nd selective histamine H-2 receptor agonist of a series of substituted 4- or 5-(2-aminoethyl)thiazoles. Quantum chemical studies on histamin e (N(pi)-H tautomer), dimaprit, and amthamine revealed that, based upo n 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 th e agonistic activities of all known (including nontautomeric) histamin e H-2 receptor agonists. Quantitative structure-activity relationship studies with a series of substituted histamine derivatives and heteroc yclic analogues support the presented model, in which the monocations in extended conformation interact with the receptor surface; their aff inities correlate with the proton association constants of the heteroa romatic nuclei. The negatively charged anchoring site for the ethylamm onium side chain of these agonists in this model is a functional group with a pK(a) value of 4.17.