Tiotidine, a classical H 2 -antagonist, presents characteristics of an inverse agonist in U937 cell line

Fernández

2016

Mol Pharmacol

H 1 and H 2 histamine receptor antagonists, although developed many decades ago, are still effective for the treatment of allergic and gastric acid-related conditions. This article focuses on novel aspects of the pharmacology and molecular mechanisms of histamine receptors that should be contemplated for optimizing current therapies, repositioning histaminergic ligands for new therapeutic uses, or even including agonists of the histaminergic system in the treatment of different pathologies such as leukemia or neurodegenerative disorders. In recent years, new signaling phenomena related to H 1 and H 2 receptors have been described that make them suitable for novel therapeutic approaches. Crosstalk between histamine receptors and other membrane or nuclear receptors can be envisaged as a way to modulate other signaling pathways and to potentiate the efficacy of drugs acting on different receptors. Likewise, biased signaling at histamine receptors seems to be a pharmacological feature that can be exploited to investigate nontraditional therapeutic uses for H 1 and H 2 biased agonists in malignancies such as acute myeloid leukemia and to avoid undesired side effects when used in standard treatments. It is hoped that the molecular mechanisms discussed in this review contribute to a better understanding of the different aspects involved in histamine receptor pharmacology, which in turn will contribute to increased drug efficacy, avoidance of adverse effects, or repositioning of histaminergic ligands.

Section: Biased Signaling At H 1 and H 2 Histamine Receptorsmentioning

confidence: 95%

“…All H 2 R antagonists that are used clinically, including cimetidine, famotidine, and ranitidine, behave as inverse agonists (Smit et al, 1996;Monczor et al, 1998). However, as with H 1 R ligands, whether inverse agonism is relevant for their therapeutic action remains to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

Current Knowledge and Perspectives on Histamine H₁and H₂Receptor Pharmacology: Functional Selectivity, Receptor Crosstalk, and Repositioning of Classic Histaminergic Ligands

Fernández

2016

Mol Pharmacol

“…However, in these cells, tiotidine, previously reported as an H2 specific antagonist, showed inverse agonist characteristics (Monczor et al, 1998). The suitability of tiotidine has been a controversial issue (van der Goot and Timmerman, 2000) because of its complex binding since studies carried out in gastric mucosal cells (Batzri and Harmon, 1986) and kidney membranes (Rising and Norris, 1985) revealed the presence of several binding sites for […”

mentioning

confidence: 99%

Tiotidine, a Histamine H2 Receptor Inverse Agonist That Binds with High Affinity to an Inactive G-Protein—Coupled Form of the Receptor. Experimental Support for the Cubic Ternary Complex Model

Fernández²,

Legnazzi³

et al. 2003

Mol Pharmacol

Knowing the importance for research and pharmacological uses of proper ligand classification into agonists, inverse agonists, and antagonists, the aim of this work was to study the behavior of tiotidine, a controversial histamine H2 receptor ligand. We found that tiotidine, described previously as an H2 antagonist, actually behaves as an inverse agonist in U-937 cells, diminishing basal cAMP levels. [3 H]Tiotidine showed two binding sites, one with high affinity and low capacity and the other with low affinity and high capacity. The former site disappeared in the presence of guanosine 5Ј-O-(3-thio)triphosphate, indicating that it belongs to a subset of receptors coupled to G-protein, showing the classic binding profile for an agonist. Considering the occupancy models developed up to now, the only one that explains tiotidine dual behavior is the cubic ternary complex (CTC) model. This model allows Gprotein to interact with the receptor even in the inactive state. We showed by theoretical simulations based on the CTC model of dose-response and binding experiments that tiotidine biases the system to a G-protein-coupled form of the receptor that is unable to evoke a response. This theoretical approach was supported by experimental results in which an unrelated Gprotein-coupled receptor that also signals through G␣ s -protein (␤ 2 -adrenoreceptor) was impeded by tiotidine. This interference clearly implies that tiotidine biases the system to G␣ s -coupled form of the H2 receptor and turns G␣ s -protein less available to interact with ␤ 2 -adrenoreceptor. These findings not only show that tiotidine is an H2 inverse agonist in U-937 cells but also provide experimental support for the CTC model.Receptors coupled to G-proteins (GPCRs) play a major role in signal transduction and are the targets for a large number of therapeutic drugs. Although much is known about signal transduction pathways, the mechanism by which ligands bind to and activate GPCRs remains unclear. In an attempt to understand such mechanisms, several occupancy models have been developed. The first theoretical model of receptor function that included G-proteins was the ternary complex model of De Léan et al. (1980) in which the receptor possesses two binding sites, one for the ligand on the extracellular side and other for the G-protein in the intracellular side. This model is a generalization of former models, in which only the free receptor and the receptor ligand complex existed, allowing

“…Stable expression of the human H2 receptor in CHO cells also resulted in an increase in basal cAMP levels, which was diminished by cimetidine, famotidine, and ranitidine as well, with potencies similar to those found for the rat H2 receptor (Alewijnse et al, 1998). Likewise, in the human promonocytic U-937 cell line we also showed that tiotidine, another ligand previously described as a H2 antagonist, actually behaves as an inverse agonist (Monczor et al, 1998).…”

Section: Histamine Receptors and Functionsmentioning

confidence: 74%

Mechanisms of inverse agonism at histamine H2 receptors – potential benefits and concerns

2006

Inflammopharmacol

Self Cite

It is well established that histamine exerts its effects by activating histamine receptors that belongs to the family of seven transmembrane G-protein coupled receptors (GPCRs). Many ligands with important therapeutic actions that had been assumed to be antagonists at histamine H2 receptor have been shown to be inverse agonists. The mechanism whereby these drugs achieve their effects seems to be not unique. Theoretical models predict at least three ways in which inverse agonists can exert their action that are supported by experimental observations. These different mechanisms have crucial consequences on basic pharmacology and clinical treatments. The pharmacological models, the feasible mechanisms of action of H2 inverse agonists, findings about molecular basis of tiotidine inverse agonism in particular, and their impact on clinical protocols will be discussed.