New model for the agonistic binding site on the histamine H sub(2)-receptor: the catalytic triad in serine proteases as a model for the binding site of histamine H sub(2)-receptor agonists

The historical model for the agonistic binding site on the histamine H sub(2)-receptor is based on a postulated activation mechanism: it has been suggested that the histamine monocation binds to the histamine H sub(2)-receptor via the formation of three hydrogen bonds. However, this model for the constitution of the agonistic binding site and the accessory activation mechanism cannot explain the weak histamine H sub(2)-activity of several other recently synthesized H sub(2)-agonists. Based on a thorough literature study and with the aid of molecular electrostatic potentials, we demonstrate that the sulfur atom present in histamine H sub(2)-agonists as dimaprit and 2-amino-5-(2-aminoethyl) thiazole does not function as a proton acceptor, which implicitly means that a tautometric shift is not a prerequisite for H sub(2)-stimulation. As a consequence, the model for the agonistic binding site is adjusted, resulting in a strong resemblance to the nature and orientation of the amino acids constituting the catalytic triad in serine proteases. Within this concept, the N super( pi )-H tautomer of histamine is the biologically active form, in contrast with the existing model in which the N super( pi )-H tautomer is the active form.