Theoretical studies on the activation mechanism of the histamine H₂‐receptor: The guanidine substitution and its role in the partial agonism of N(alpha)‐guanylhistamine

Histamine [2‐(4‐imidazolyl)ethylamine, HA] is a neurotransmitter that was shown to act on two different receptors, the H₁‐ and H₂‐receptors. Structure‐activity considerations made it possible to identify molecular determinants for the action of drugs on the H₂‐receptors. A key probe of the resulting hypothesis relating molecular structure to activity on these receptors is its ability to explain the action of partial agonists which are pharmacologic intermediates between agonists and antagonists. We therefore studied the molecular structure and properties of N (alpha)‐guanylhistamine [2‐(4‐imidazolyl)ethylguanidine, NAGHA], which differs from histamine by a substitution of the side chain amine by a guanidine group. To understand how the substitution with the guanidine determines this change in properties, we also studied separately the molecular structure of guanidine and guanidinium in various tautomeric forms, with geometry optimization and several different basis sets. The results suggest the preferred site of protonation and interaction of NAGHA with the negative site of the H₂‐receptor. For N(3)‐H and N(1)‐H tautomers of the neutral and cationic species of NAGHA, we did complete geometry optimization at the all electron Hartree‐Fock level with the STO‐3G basis set. The results support the working hypothesis that, like HA, NAGHA monocation approaches the H₂‐receptor as the N(3)‐H tautomer. Neutralization at the anionic site also shifts the preference in tautomeric equilibrium toward the N(1)‐H form, thereby triggering the charge relay sequence that was proposed as an activation mechanism of the H₂‐receptor. The dependence of these mechanisms of interaction with the receptor on the conformation of the side chain as well as on the position at which the negative receptor site interacts with the guanyl group suggests explanations both for the lower affinity and for the partial agonist properties of NAGHA at the H₂‐receptor.