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J Giraldo

Publications and source records attributed to J Giraldo.

22 records · Page 2Linked to original sources
PubMed1992

Theoretical studies on the histamine H2 receptor: molecular mechanism of action of antagonists.

The previously defined sites in the histamine H2 receptor model [Mol. Pharmacol. 40:980-987 (1991)] were used to elucidate the pharmacological mechanism of action of compounds that act as antagonists at the receptor. In this model, a formate anion is used both as the negative site at which the histamine cation is anchored to the receptor and as a proton acceptor site. An ammonium cation is used as a proton donor site. The proposed model of recognition of cimetidine, tiotidine, and ranitidine suggests that the monocationic form of the antagonists is the most favorable species to bind the receptor. Moreover, the mode of recognition follows the same trends obtained for compounds that act as agonists; the protonated site of the molecule, i.e., imidazolium in cimetidine, guanidinium in tiotidine, or substituted ammonium in ranitidine, anchors at the negative site of the receptor, whereas the nonbasic part, i.e., cyanoguanidine in cimetidine and tiotidine and nitrodiaminoethene in ranitidine, is located between the proton donor and acceptor sites. An energetic analysis of the interaction between the antagonists and the receptor model, including the energies of ligand desolvation, shows that histamine cannot compete effectively with cimetidine, tiotidine, or ranitidine for binding to the H2 receptor. The predicted order of antagonist potencies, based on differences of formation enthalpies (delta delta H1), reproduces qualitatively the experimental rank order.

Cimetidine↗
PubMed1991

Theoretical studies on the histamine H2 receptor: construction of a receptor model based on the structural properties of dimaprit and N alpha-guanylhistamine.

A histamine H2 receptor model was constructed based on the receptor sites previously proposed by Weinstein et al. [Mol. Pharmacol. 29:28-33 (1986)]. In this model, a glutamate or aspartate residue, simulated by a formate anion, is proposed both as the negative site at which the histamine cation is anchored to the receptor and as a proton-acceptor site. A proton-donor site, simulated by an ammonium cation, is proposed to model either a lysine, arginine, or histidine residue. The simulation of the activation mechanism of the histamine H2 receptor, inside the proposed receptor model, includes structure optimizations of stationary points and transition states with a split valence basis set. The proton movement from the proton donor site to the proton acceptor site, mediated by the imidazole ring of histamine, was found to be sequential in the potential energy surface. Results of the calculations reveal that both proton transfers are feasible from an energetical point of view. However, the proton movement from N(3) to the proton acceptor site has a higher energy of activation and, therefore, will be the rate-limiting step in the starting process that triggers the cascade of events that finally leads to a biological response. This model also provides a basis for explaining the molecular determinants of the pharmacological activity of N alpha-guanylhistamine. The structural properties of the guanidinium group allow N alpha-guanylhistamine to interact with the proposed receptor in two different modes. The proton-relay process, proposed as the trigger of the activation of the histamine H2 receptor, is likely to occur in only one of these binding modes. In the other case, N alpha-guanylhistamine acts as an antagonist because the barrier to proton transfer in this mode is too high. The partial agonism of N alpha-guanylhistamine is related to the ability of the drug to bind with the receptor in two different modes with similar affinity. An energetic analysis of the interaction between of ligand and the receptor model, including the energies of ligand desolvation, shows that histamine can compete with N alpha-guanylhistamine for the binding to the H2 receptor.

Computer Simulation↗