Similar Mode Of Action Research Articles

Evidence from pharmacology and pathophysiology suggests that chemicals with dissimilar mechanisms of action could be of bigger concern in the toxicological risk assessment of chemical mixtures than chemicals with a similar mechanism of action

Mathematical models have been developed for the toxicological risk assessment of chemical mixtures. However, exposure data as well as single chemical toxicological data are required for these models. When addressing this data need, it could be attractive to focus on chemicals with similar mechanisms of action, similar modes of action or with common target organs. In the European Union, efforts are currently being made to subgroup chemicals according to this need. However, it remains to be determined whether this is the best strategy to obtain data for risk assessment. In conditions such as cancer or HIV, it is generally recognised that pharmacological combination therapy targeting different mechanisms of action is more effective than a strategy where only one mechanism is targeted. Moreover, in diseases such as acute myocardial infarction and congestive heart failure, several organ systems concomitantly contribute to the pathophysiology, suggesting that a grouping based on common target organs may also be inefficient. A better option may be to prioritise chemicals on the basis of potency and risk of exposure. In conclusion, there are arguments to suggest that we should concomitantly consider all targets that a chemical can affect in the human body and not merely a subset.

The polyene antifungals, amphotericin B and nystatin, cause cell death in Saccharomyces cerevisiae by a distinct mechanism to amphibian-derived antimicrobial peptides

BackgroundThere is a pressing need to identify novel antifungal drug targets to aid in the therapy of life-threatening mycoses and overcome increasing drug resistance. Identifying specific mechanisms of action of membrane-interacting antimicrobial drugs on the model fungus Saccharomyces cerevisiae is one avenue towards addressing this issue. The S. cerevisiae deletion mutants Δizh2, Δizh3, Δaif1 and Δstm1 were demonstrated to be resistant to amphibian-derived antimicrobial peptides (AMPs). The purpose of this study was to examine whether AMPs and polyene antifungals have a similar mode of action; this was done by comparing the relative tolerance of the mutants listed above to both classes of antifungal.FindingsIn support of previous findings on solid media it was shown that Δizh2 and Δizh3 mutants had increased resistance to both amphotericin B (1–2 μg ml−1) and nystatin (2.5 – 5 μg ml−1) in liquid culture, after acute exposure. However, Δaif1 and Δstm1 had wild-type levels of susceptibility to these polyenes. The generation of reactive oxygen species (ROS) after exposure to amphotericin B was also reduced in Δizh2 and Δizh3. These data indicated that polyene antifungal and AMPs may act via distinct mechanisms of inducing cell death in S. cerevisiae.ConclusionsFurther understanding of the mechanism(s) involved in causing cell death and the roles of IZH2 and IZH3 in drug susceptibility may help to inform improved drug design and treatment of fungal pathogens.

Combining growth-promoting genes leads to positive epistasis in Arabidopsis thaliana.

Several genes positively influence final leaf size in Arabidopsis when mutated or overexpressed. The connections between these growth regulators are still poorly understood although such knowledge would further contribute to understand the processes driving leaf growth. In this study, we performed a combinatorial screen with 13 transgenic Arabidopsis lines with an increased leaf size. We found that from 61 analyzed combinations, 39% showed an additional increase in leaf size and most resulted from a positive epistasis on growth. Similar to what is found in other organisms in which such an epistasis assay was performed, only few genes were highly connected in synergistic combinations as we observed a positive epistasis in the majority of the combinations with samba, BRI1(OE) or SAUR19(OE). Furthermore, positive epistasis was found with combinations of genes with a similar mode of action, but also with genes which affect distinct processes, such as cell proliferation and cell expansion.DOI: http://dx.doi.org/10.7554/eLife.02252.001.

Mantra 2.0: an online collaborative resource for drug mode of action and repurposing by network analysis

Elucidation of molecular targets of a compound [mode of action (MoA)] and its off-targets is a crucial step in drug development. We developed an online collaborative resource (MANTRA 2.0) that supports this process by exploiting similarities between drug-induced transcriptional profiles. Drugs are organized in a network of nodes (drugs) and edges (similarities) highlighting 'communities' of drugs sharing a similar MoA. A user can upload gene expression profiles before and after drug treatment in one or multiple cell types. An automated processing pipeline transforms the gene expression profiles into a unique drug 'node' embedded in the drug-network. Visual inspection of the neighbouring drugs and communities helps in revealing its MoA and to suggest new applications of known drugs (drug repurposing). MANTRA 2.0 allows storing and sharing user-generated network nodes, thus making MANTRA 2.0 a collaborative ever-growing resource. The web tool is freely available for academic use at http://mantra.tigem.it.

Synthesis and biological activities of novel methyl xanthine derivatives

Caffeine is one of methyl xanthine compounds, which has the similar mode of action as ryanodine receptor insecticide. In order to find novel and efficient insecticide, structural modification of certain methyl xanthine compounds was made by introducing some common pesticidal active moieties into the structure of caffeine. Eleven novel methyl xanthine compounds were synthesized and characterized by 1H nuclear magnetic resonance(1H NMR), elemental analylsis or high-resolution mass spectrometry(HRMS). According to the biological activity results, it was found that these new compounds show moderate activity towards Mythimna separata Walker and Culex pipiens pallens. For example, compound 2d shows a lethality rate of 40% at 200 mg/L towards Mythimna separata Walker, compounds 2i and 2f show 56.7% and 53.3% lethality rates at 2 mg/L towards Culex pipiens pallens, which are all better than caffeine. In addition, some compounds of them show moderate antifungal activity to some plant pathogenous fungi.

Multikinase Inhibitors for the Treatment of Progressive, Metastatic Medullary Thyroid Cancer - An Evolving Paradigm.

Medullary thyroid cancer (MTC) is an uncommon type of thyroid cancer, representing around 4 % of the all thyroid cancers, and is a challenging malignancy. So far, surgery has been the only curative treatment and until recently there have been no effective medications. Within the past 5 years, multi-targeted kinase inhibitors have emerged that have shown convincing efficacy against such tumours. These drugs have changed the landscape in MTC treatment by providing effective medication for the first time. The modes of action of these drugs differ, but most target RET, a tyrosine kinase shown to play an important role in the pathobiology of MTC, as well as other receptors including vascular endothelial growth factor receptors (VEGFRs), epidermal growth factor receptor (EGFR) and the hepatocyte growth factor receptor MET. Two agents in this class, vandetanib and cabozantinib, have demonstrated efficacy and safety in phase III trials and have consequently received regulatory approval. Other therapies for MTC treatment, including some with similar modes of action, are also in early development.

Update on Short-Acting vs. Long-Acting PDE5i + Life-Style Changes vs. PDE5i

The medical management of erectile dysfunction(ED) has evolved greatly over the past 20 years. Prior to the early 80’s we were able to offer patients one of two definitive surgical therapies for the management of their erectile dysfunction: implantation of penile prosthesis and penile revascularization. The first approved phosphodiesterase inhibitors (PDE5i) for the treatment of ED was sildenafil citrate (1998). Currently, there are four FDA approved oral medications indicated for the treatment of ED (sildenafil, vardenafil, tadalafil and avanafil), all of predominantly inhibit PDE5. Despite their similar modes of action, PDE5i differ in their biochemical properties, pharmacokinetic profiles, and clinical performance. Most distinctive is their half-life, with sildenafil, vardenafil and avanafil having half-lives of approximately 4-5 hours, compared with tadalafil, with a half-life of 17.5 hours. The median time to maximum concentration (t max) is 30 minutes for avanafil, 1 hour for sildenafil and vardenafil, and 2 hours for tadalafil. The abundance of choices poses the question, which PDE-5 inhibitor? relevant for clinicians, patients and their partners. A significant percentage of men initiating treatment will ultimately switch between inhibitors or discontinue therapy (poor compliance). Properly counseling patients and their partners as to the appropriate treatment choice is paramount to optimizing compliance. It is widely accepted that there are no significant differences in the safety and efficacy of the 4 PDE5i, although avanafil has shown great promise in reducing the typical side effects. Lifestyle modifications should be certainly considered an integral part of the treatment regimen for ED, both independently and in conjunction with other management options. The risk of developing ED is closely associated with the presence of co-morbidities such as diabetes, cardiovascular disease, and metabolic syndrome. Prevention or appropriate treatment of these disease states, can positively impact sexual health.

Understanding off-label use and the new challenges

As there are several thousands of rare disorders and only some tents of orphan drugs authorized in Europe, off-label use of medicinal products occurs frequently in the diagnosis, prevention and treatment of rare diseases. Off-label use is the use of a medicinal product for another indication, another patient group, another dose or by another route of administration as indicated in the package insert. This so-called off-label use is suggested by a similar mode of action or a similar pathology. The competent authorities complain about this therapeutic usage because there is no evidence of their safety and efficacy. Payers hesitate to reimburse this non-validated use. The only responsible person for this use is the prescriber. Sometimes the patient will be asked to sign an informed consent. Normalization of this off-label use can only be done by the sponsor not by the medical profession or the patient organization. Pharmaceutical companies are not allowed to mention the off-label use to the medical profession: recently settlements are reached against companies to resolve allegations of off-label promotion of their orphan pharmaceutical products (Tobi, Trisenox, Xyrem). Some pharmaceutical companies bring the old substance on the market as a so-called new “repurposed” or “rediscovered” medicinal product with a higher price (Litak, Quenobilan, Savene, Xenbilox). When the medicinal product is taken from the market (deflazacort, mexiletine) the off-label users lose their only treatment. At the faculty of pharmacy of the University in Leuven, a group of students performed in-depth interviews to all the stakeholders in this process and identified the main obstacles to regularization. The Belgian Health Care Knowledge Center [https://kce.fgov.be/] will further explore these recommendations and give advice to the public authorities to take further actions. The Belgian Minister of Health already proposed a Royal Decree to reimburse some off-label use under restricted circumstances such as “unmet medical need”. EURORDIS has launched an off-label questionnaire within their members to explore the impact of this off-label prescribing for patients with rare diseases: http://www.ataxia.org.uk/news.php/234/off-label-use-of-medicines-information-needed-from-people-with-ataxia.

Endocrine disruption: Fact or urban legend?

Endocrine disruptors (EDs) are substances that cause adverse health effects via endocrine-mediated mechanisms in an intact organism or its progeny or (sub) populations. Purported EDCs in personal care products include 4-MBC (UV filter) or parabens that showed oestrogenic activity in screening tests, although regulatory toxicity studies showed no adverse effects on reproductive endpoints. Hormonal potency is the key issue of the safety of EDCs. Oestrogen-based drugs, e.g. the contraceptive pill or the synthetic oestrogen DES, possess potencies up to 7 orders of magnitude higher than those of PCP ingredients; yet, in utero exposure to these drugs did not adversely affect fertility or sexual organ development of offspring unless exposed to extreme doses. Additive effects of EDs are unlikely due to the multitude of mechanisms how substances may produce a hormone-like activity; even after uptake of different substances with a similar mode of action, the possibility of additive effects is reduced by different absorption, metabolism and kinetics. This is supported by a number of studies on mixtures of chemical EDCs. Overall, despite of 20 years of research a human health risk from exposure to low concentrations of exogenous chemical substances with weak hormone-like activities remains an unproven and unlikely hypothesis.

Molecular docking: A potential tool to aid ecotoxicity testing in environmental risk assessment of pharmaceuticals

A cocktail of human pharmaceuticals pollute aquatic environments and there is considerable scientific uncertainty about the effects that this may have on aquatic organisms. Human drug target proteins can be highly conserved in non target species suggesting that similar modes of action (MoA) may occur. The aim of this work was to explore whether molecular docking offers a potential tool to predict the effects of pharmaceutical compounds on non target organisms. Three highly prescribed drugs, diclofenac, ibuprofen and levonorgestrel which regularly pollute freshwater environments were used as examples. Their primary drug targets are cyclooxygenase 2 (COX2) and progesterone receptor (PR). Molecular docking experiments were performed using these drugs and their primary drug target homologues for Danio rerio, Salmo salar, Oncorhynchus mykiss, Xenopus tropicalis, Xenopus laevis and Daphnia pulex. The results show that fish and frog COX2 enzymes are likely to bind diclofenac and ibuprofen in the same way as humans but that D. pulex would not. Binding will probably lead to inhibition of COX function and reduced prostaglandin production. Levonorgestrel was found to bind in the same binding pocket of the progesterone receptor in frogs and fish as the human form. This suggests implications for the fecundity of fish and frogs which are exposed to levonorgestrel. Chronic ecotoxicological effects of these drugs reported in the literature support these findings. Molecular docking may provide a valuable tool for ecotoxicity tests by guiding selection of test species and incorporating the MoA of drugs for relevant chronic test end points in environmental risk assessments.

Improving Pharmacokinetic-Pharmacodynamic Modeling to Investigate Anti-Infective Chemotherapy with Application to the Current Generation of Antimalarial Drugs

Mechanism-based pharmacokinetic-pharmacodynamic (PK/PD) modelling is the standard computational technique for simulating drug treatment of infectious diseases with the potential to enhance our understanding of drug treatment outcomes, drug deployment strategies, and dosing regimens. Standard methodologies assume only a single drug is used, it acts only in its unconverted form, and that oral drugs are instantaneously absorbed across the gut wall to their site of action. For drugs with short half-lives, this absorption period accounts for a significant period of their time in the body. Treatment of infectious diseases often uses combination therapies, so we refined and substantially extended the PK/PD methodologies to incorporate (i) time lags and drug concentration profiles resulting from absorption across the gut wall and, if required, conversion to another active form; (ii) multiple drugs within a treatment combination; (iii) differing modes of action of drugs in the combination: additive, synergistic, antagonistic; (iv) drugs converted to an active metabolite with a similar mode of action. This methodology was applied to a case study of two first-line malaria treatments based on artemisinin combination therapies (ACTs, artemether-lumefantrine and artesunate-mefloquine) where the likelihood of increased artemisinin tolerance/resistance has led to speculation on their continued long-term effectiveness. We note previous estimates of artemisinin kill rate were underestimated by a factor of seven, both the unconverted and converted form of the artemisinins kill parasites and the extended PK/PD methodology produced results consistent with field observations. The simulations predict that a potentially rapid decline in ACT effectiveness is likely to occur as artemisinin resistance spreads, emphasising the importance of containing the spread of artemisinin resistance before it results in widespread drug failure. We found that PK/PD data is generally very poorly reported in the malaria literature, severely reducing its value for subsequent re-application, and we make specific recommendations to improve this situation.

Bacteriocins In Poultry Nutrition – A Review / Bakteriocyny w żywieniu drobiu – artykuł przeglądowy

Abstract In recent years, a number of studies have shown a close relationship between broiler performance, health and the gastrointestinal microbiota. However, taking the complexity and biodiversity of the micro-ecosystem into consideration, a manipulation of the microbiota in a way that is profitable both for the host bird and for the farmer seems a difficult goal to achieve. Bacteriocins are extracellular proteinaceous compounds, synthesized by many bacterial species. Due to their different bacteriostatic effects, they have been used in human nutrition for decades. However, limited information is available regarding their effects in poultry, even though that similar mode of action as in other animals is possible. Therefore, the aim of the present review is to discuss present bacteriocin classification, mode of action and their potential role in poultry nutrition.

Combination effects of amphetamines under hyperthermia - the role played by oxidative stress

Rise in body temperature is a life-threatening consequence of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) abuse. We evaluated the impact of hyperthermia on the cytotoxicity of combinations of MDMA and three other amphetamines, often co-ingested. For this, Hep G2 cells were exposed to MDMA, d-amphetamine, methamphetamine and 4-methylthioamphetamine, individually or combined, at 40.5 °C. The results were compared with normothermia data (37.0 °C). Mixture additivity expectations were calculated by independent action and concentration addition (CA) models. To delineate the mechanism(s) underlying the elicited effects, a range of stress endpoints was evaluated, including quantification of reactive oxygen/nitrogen species (ROS/RNS), lipid peroxidation, reduced/oxidized glutathione (GSH/GSSG), ATP and mitochondrial membrane potential (Δψm) changes. Our data show that, in hyperthermia, amphetamines acted additively and mixture effects were accurately predicted by CA. At 40.5 °C, even slight increases in the concentrations of each drug/mixture promoted significant rises in cytotoxicity, which quickly shifted from roughly undetectable to maximal mortality. Additionally, the increase of RNS/ROS production, decrease of GSH, ATP depletion and mitochondrial impairment were exacerbated under hyperthermia. Importantly, when equieffective cytotoxic concentrations of the mixture and individual amphetamines were compared for all tested stress endpoints, mixture effects did not deviate from those elicited by individual treatments, suggesting that these amphetamines have a similar mode of action, which is not altered in combination. Concluding, our data indicate that amphetamine mixtures produce deleterious effects, even when individual drugs are combined at negligible concentrations. These effects are strongly exacerbated in hyperthermia, emphasizing the potential increased risks of ecstasy intake, especially when hyperthermia occurs concurrently with polydrug abuse.

Concern-driven integrated approaches to nanomaterial testing and assessment – report of the NanoSafety Cluster Working Group 10

Bringing together topic-related European Union (EU)-funded projects, the so-called “NanoSafety Cluster” aims at identifying key areas for further research on risk assessment procedures for nanomaterials (NM). The outcome of NanoSafety Cluster Working Group 10, this commentary presents a vision for concern-driven integrated approaches for the (eco-)toxicological testing and assessment (IATA) of NM. Such approaches should start out by determining concerns, i.e., specific information needs for a given NM based on realistic exposure scenarios. Recognised concerns can be addressed in a set of tiers using standardised protocols for NM preparation and testing. Tier 1 includes determining physico-chemical properties, non-testing (e.g., structure–activity relationships) and evaluating existing data. In tier 2, a limited set of in vitro and in vivo tests are performed that can either indicate that the risk of the specific concern is sufficiently known or indicate the need for further testing, including details for such testing. Ecotoxicological testing begins with representative test organisms followed by complex test systems. After each tier, it is evaluated whether the information gained permits assessing the safety of the NM so that further testing can be waived. By effectively exploiting all available information, IATA allow accelerating the risk assessment process and reducing testing costs and animal use (in line with the 3Rs principle implemented in EU Directive 2010/63/EU). Combining material properties, exposure, biokinetics and hazard data, information gained with IATA can be used to recognise groups of NM based upon similar modes of action. Grouping of substances in return should form integral part of the IATA themselves.

Determination of Toxicant Mode of Action by Augmented Top Priority Fragment Class

Theoretical models can be an efficient tool to assess compound toxicity as an alternative to experimental determinations. Their application must follow some requirements that include the possibility of understanding the rationale that supports the prediction; here, the determination of the mode of action (MOA) is important. A combination of similarity and reactivity analysis has been applied to group chemical compounds with the aim at selecting groups that share structure and electronic state. The model is not based on experimental data but only on structural features. The result is a number of groups that contains similar compounds with similar reactivity and, possibly, similar MOA. The comparison of these groups to the experimentally determined MOAs available for the EPAFHAM database permits the discussion of the validity of both the model and the experimental data.

Multiple actions of φ-LITX-Lw1a on ryanodine receptors reveal a functional link between scorpion DDH and ICK toxins

We recently reported the isolation of a scorpion toxin named U1-liotoxin-Lw1a (U1-LITX-Lw1a) that adopts an unusual 3D fold termed the disulfide-directed hairpin (DDH) motif, which is the proposed evolutionary structural precursor of the three-disulfide-containing inhibitor cystine knot (ICK) motif found widely in animals and plants. Here we reveal that U1-LITX-Lw1a targets and activates the mammalian ryanodine receptor intracellular calcium release channel (RyR) with high (fM) potency and provides a functional link between DDH and ICK scorpion toxins. Moreover, U1-LITX-Lw1a, now described as ϕ-liotoxin-Lw1a (ϕ-LITX-Lw1a), has a similar mode of action on RyRs as scorpion calcines, although with significantly greater potency, inducing full channel openings at lower (fM) toxin concentrations whereas at higher pM concentrations increasing the frequency and duration of channel openings to a submaximal state. In addition, we show that the C-terminal residue of ϕ-LITX-Lw1a is crucial for the increase in full receptor openings but not for the increase in receptor subconductance opening, thereby supporting the two-binding-site hypothesis of scorpion toxins on RyRs. ϕ-LITX-Lw1a has potential both as a pharmacological tool and as a lead molecule for the treatment of human diseases that involve RyRs, such as malignant hyperthermia and polymorphic ventricular tachycardia.

Fragments of the Bacterial Toxin Microcin B17 as Gyrase Poisons

Fluoroquinolones are very important drugs in the clinical antibacterial arsenal; their success is principally due to their mode of action: the stabilisation of a gyrase-DNA intermediate (the cleavage complex), which triggers a chain of events leading to cell death. Microcin B17 (MccB17) is a modified peptide bacterial toxin that acts by a similar mode of action, but is unfortunately unsuitable as a therapeutic drug. However, its structure and mechanism could inspire the design of new antibacterial compounds that are needed to circumvent the rise in bacterial resistance to current antibiotics. Here we describe the investigation of the structural features responsible for MccB17 activity and the identification of fragments of the toxin that retain the ability to stabilise the cleavage complex.

Modeling mixtures of thyroid gland function disruptors in a vertebrate alternative model, the zebrafish eleutheroembryo

Maternal thyroxine (T4) plays an essential role in fetal brain development, and even mild and transitory deficits in free-T4 in pregnant women can produce irreversible neurological effects in their offspring. Women of childbearing age are daily exposed to mixtures of chemicals disrupting the thyroid gland function (TGFDs) through the diet, drinking water, air and pharmaceuticals, which has raised the highest concern for the potential additive or synergic effects on the development of mild hypothyroxinemia during early pregnancy. Recently we demonstrated that zebrafish eleutheroembryos provide a suitable alternative model for screening chemicals impairing the thyroid hormone synthesis. The present study used the intrafollicular T4-content (IT4C) of zebrafish eleutheroembryos as integrative endpoint for testing the hypotheses that the effect of mixtures of TGFDs with a similar mode of action [inhibition of thyroid peroxidase (TPO)] was well predicted by a concentration addition concept (CA) model, whereas the response addition concept (RA) model predicted better the effect of dissimilarly acting binary mixtures of TGFDs [TPO-inhibitors and sodium-iodide symporter (NIS)-inhibitors]. However, CA model provided better prediction of joint effects than RA in five out of the six tested mixtures. The exception being the mixture MMI (TPO-inhibitor)-KClO4 (NIS-inhibitor) dosed at a fixed ratio of EC10 that provided similar CA and RA predictions and hence it was difficult to get any conclusive result. There results support the phenomenological similarity criterion stating that the concept of concentration addition could be extended to mixture constituents having common apical endpoints or common adverse outcomes.

A Systematic In Silico Search for Target Similarity Identifies Several Approved Drugs with Potential Activity against the Plasmodium falciparum Apicoplast

Most of the drugs in use against Plasmodium falciparum share similar modes of action and, consequently, there is a need to identify alternative potential drug targets. Here, we focus on the apicoplast, a malarial plastid-like organelle of algal source which evolved through secondary endosymbiosis. We undertake a systematic in silico target-based identification approach for detecting drugs already approved for clinical use in humans that may be able to interfere with the P. falciparum apicoplast. The P. falciparum genome database GeneDB was used to compile a list of ≈600 proteins containing apicoplast signal peptides. Each of these proteins was treated as a potential drug target and its predicted sequence was used to interrogate three different freely available databases (Therapeutic Target Database, DrugBank and STITCH3.1) that provide synoptic data on drugs and their primary or putative drug targets. We were able to identify several drugs that are expected to interact with forty-seven (47) peptides predicted to be involved in the biology of the P. falciparum apicoplast. Fifteen (15) of these putative targets are predicted to have affinity to drugs that are already approved for clinical use but have never been evaluated against malaria parasites. We suggest that some of these drugs should be experimentally tested and/or serve as leads for engineering new antimalarials.

Molecular insights into the AT1 antagonism based on biophysical and in silico studies of telmisartan

AT1 antagonists (SARTANs) constitute one of the most successful classes of antihypertensive agents. These molecules interfere with the renin angiotensin system by preventing the vasoconstrictive hormone angiotensin II from binding onto the AT1 receptor. It is proposed that SARTANs exert their biological action by inserting into the lipid membrane and then diffuse to the active site of AT1 receptor. In this article, the conformational properties of telmisartan are analyzed both in solution and in the active site of the AT1 receptor using conformational analysis, molecular docking, Molecular Dynamics (MD) simulations, and in silico Ala-scanning mutagenesis studies. Combined results reveal telmisartan’s crucial structural characteristics and classify the importance of receptor’s amino acids for ligand binding. Since telmisartan is exerting its activity on a transmembrane receptor, Differential Scanning Calorimetry was applied to study the drug effects in lipid bilayers mimicking the biological membrane environment. Of paramount importance, is the finding that telmisartan exerted similarities but also significant differences with other AT1 antagonists on the basis of their interaction with lipid bilayers and subsequent docking into the active site. This could in part explain their similar mode of action and in parallel their distinct pharmacological profile.