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metoprolol ER + hydrochlorothiazide (Selopress Zok / Dutoprol)

✓ Approved

AstraZeneca UK Limited · ADRB1 · Small Molecule

What is metoprolol ER + hydrochlorothiazide?

metoprolol ER + hydrochlorothiazide is a small molecule developed by AstraZeneca UK Limited. It is approved for therapeutic indications via oral (po).

Drug Profile

Brand NamesSelopress Zok, Dutoprol
CompanyAstraZeneca UK Limited
Drug ClassSmall Molecule
Molecular TargetADRB1
RouteOral (PO)
StatusApproved
Sources: ClinicalTrials.gov, AstraZeneca UK Limited

Mechanism of Action

Molecular Targets

metoprolol ER + hydrochlorothiazide acts on 1 molecular target:

ADRB1adrenoceptor beta 1 (B1AR, RHR)
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Therapeutic Indications

metoprolol ER + hydrochlorothiazide is developed for 1 unique indication across 1 therapeutic area.

Therapeutic AreaConditionPhase
Vascular disordersHypertension✓ Approved

Related Research Articles

PubMedCell discovery2026-11-11

ER-mitochondria contacts orchestrate mitochondrial transport via C19orf12.

Pei Xiayuhe X, Zhang Shuqian S, Li Peiyang P, Wu Yutong Y et al.

Endoplasmic reticulum (ER)-mitochondria contact sites facilitate lipid transfer, calcium signaling, and mitochondrial division; however, their role in mitochondrial transport remains unclear. Here, we identify hereditary spastic paraplegia (HSP)-associated protein C19orf12 as an ER-anchored regulator of mitochondrial trafficking. The loss of C19orf12 leads to perinuclear mitochondrial clustering in cells, impaired anterograde transport in neurons, and progressive locomotor dysfunction in mice that recapitulates key features of HSP in humans. Mechanistically, C19orf12 forms a discrete complex with the mitochondrial Rho GTPase Miro1 and the Kinesin-1 motor Kif5b, thereby providing a molecular link between ER-mitochondria contacts and microtubule-based anterograde transport. Ca2+ also modulated C19orf12-Miro1 behavior in vitro and showed a biphasic association with mitochondrial motility in live cells. Therefore, our findings establish ER‒mitochondria contact sites as logistical hubs for Kinesin-1 motor loading and highlight the importance of the Ca2+-tunable C19orf12 scaffold in sustaining directional mitochondrial transport, providing a mechanistic framework for how C19orf12 loss may contribute to neurodegeneration.

PMID 43009488
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PubMedAdvanced healthcare materials2026-11-11

Sequential Modeling of Fibrotic and Mineralizing Osteoarthritis-Like Remodeling in hDPSC-Derived Cartilage Microtissues.

Huang Xinqi X, Tao Yun Y, Huang Zhimao Z, Zhao Zhihe Z et al.

Osteoarthritis (OA) involves alterations in cartilage mechanics, matrix composition, and mineralization, yet in vitro models that resolve remodeling transitions remain limited. Scaffold-free cartilage microtissues derived from human dental pulp stem cells (hDPSCs) are subjected to sequential dynamic rocking culture and triiodothyronine (T3) treatment. Dynamic rocking produces superficial Col I-positive fibrotic and matrix-degrading changes, whereas T3 induces proteoglycan loss, increased Col I and MMP13, irregular mineral deposition, and altered nanomechanical properties, defining a mixed terminal catabolic and mineralizing OA-like state. Transcriptomic profiling shows stage-associated reorganization rather than uniform pathway activation. In T3-treated microtissues, ATF6-associated ER-stress abnormalities include ER cisternal dilation and increased ATF6 signal. Targeted ATF6 knockdown reduces ATF6 signal, ER dilation, extracellular-matrix disorganization, and ER-stress/proteostasis and inflammatory/catabolic transcriptional module scores, supporting ATF6-associated signaling as a functionally relevant component of this degenerative state. In mouse temporomandibular joint and knee OA models, intra-articular Ad-shATF6 is associated with partial cartilage preservation and subchondral-bone indices shifted toward control ranges.

PMID 43012460
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PubMedThe Biochemical journal2026-11-11

Ribosomal RNA depurination prevents the unfolded protein response through translation inhibition.

Prashar Tanya T, Hudak Katalin A KA

Many newly translated proteins are targeted to the endoplasmic reticulum (ER) for folding, processing and transport to extracellular spaces. The unfolded protein response (UPR), mediated by the ER stress sensor Ire1 that splices mRNA of transcription factor Hac1, is activated when unfolded proteins accumulate. However, it remains unclear how ribosome integrity, through its effects on translation, controls UPR. To address this question, we expressed pokeweed antiviral protein (PAP), an rRNA N-glycosylase that depurinates 25S rRNA in Saccharomyces cerevisiae. We compared the effect of PAP with an enzymatically inactive mutant PAPx, as both proteins are targeted to the ER during translation, but only one damages ribosomes. RNA sequencing across a six-hour time course revealed enrichment of the ER protein processing pathway and selective upregulation of UPR-related genes in PAPx-expressing cells, but not in PAP-expressing cells. PAPx expression also increased HAC1 splicing, whereas PAP did not, even after tunicamycin treatment. Additionally, Ire1 remained inactive, as shown by lack of Ire1-2xGFP oligomerization viewed by confocal microscopy. Absence of UPR activation in PAP-expressing cells was correlated with reduced azidohomoalanine (methionine analog) incorporation into membrane-associated proteins, consistent with reduced protein flux into the ER. Our findings support a new model describing how rRNA depurination inhibits UPR upstream of Ire1 activation by reducing translational capacity, which maintains Ire1 in an inactive state. Therefore, ribosome integrity influences UPR activation by controlling translation and membrane-associated protein synthesis.

PMID 43012403
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PubMedNature communications2026-11-11

Luminal geometry and coiled coil length determine submembrane localization of type II transmembrane Golgi proteins.

Wong Jing Xue JX, Hübner Barbara B, Mahajan Divyanshu D, Tie Hieng Chiong HC et al.

We previously showed that transmembrane proteins laterally partition within Golgi cisternae: trafficking components (e.g., GPP130, a type II transmembrane protein) are enriched at the cisternal rim, whereas Golgi enzymes localize to the cisternal interior. However, the underlying mechanism was unclear. We found that the luminal juxtamembrane coiled coil of GPP130 is necessary and sufficient for rim localization, with coiled coil length, rather than sequence identity, determining partitioning. When retargeted to the ER, GPP130 preferentially localized to ER sheet rims and was partially excluded from the nuclear envelope, an exclusion reduced upon nuclear envelope expansion. Cryo-electron tomography revealed that the intraluminal widths of Golgi cisternal interiors, some ER sheets, and the nuclear envelope are smaller than the predicted coiled coil length. Two additional type II Golgi transmembrane proteins with long luminal juxtamembrane coiled coils similarly localized to cisternal rims. These findings identify intraluminal width as a mechanism governing the lateral partitioning of type II transmembrane proteins with long luminal coiled coils.

PMID 43009502
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PubMedSkeletal muscle2026-11-11

MFN2 alleviates mitochondrial calcium overload in sepsis-induced myopathy by modulating GRP75-VDAC1 interaction.

Li Xuexin X, He Fei F, Wang Yun Y, Sun Bowen B et al.

Sepsis-induced myopathy (SIM) is characterized by skeletal muscle dysfunction associated with mitochondrial calcium overload. The mitochondria-associated endoplasmic reticulum membrane (MAM) plays a crucial role in mediating mitochondrial calcium uptake. Although MFN2 and the IP3R-GRP75-VDAC1 complex have each been implicated in mitochondrial calcium regulation, their respective contributions and potential interplay in the pathogenesis of SIM remain poorly understood. A murine sepsis model was established by cecal ligation and puncture (CLP). Skeletal muscle function was assessed by compound muscle action potential (CMAP) recording and forelimb grip strength testing. Gastrocnemius muscle histology was evaluated by H&E and WGA staining. Tibialis anterior muscles were analyzed by immunofluorescence and transmission electron microscopy (TEM) to characterize MAM ultrastructure. Protein expression was quantified by western blotting, and MFN2 mRNA levels were measured by qPCR. Co-immunoprecipitation was performed to assess GRP75-VDAC1 protein interaction. Mitochondrial and cytoplasmic calcium levels were monitored using Rhod-2 AM and Fluo-4 AM, respectively. Sepsis induced skeletal muscle atrophy and dysfunction both in vivo and in vitro. IP3R-dependent calcium transfer at MAM was associated with pathological mitochondrial calcium overload, and pharmacological IP3R inhibition with 2-APB attenuated mitochondrial calcium uptake and ameliorated muscle atrophy. Concurrently, sepsis-induced MFN2 downregulation was associated with reduced ER-mitochondria distance, further promoting mitochondrial calcium overload. AAV-mediated MFN2 overexpression restored ER-mitochondria distance and was associated with reduced VDAC1 protein expression, attenuated GRP75-VDAC1 interaction, collectively contributing to mitigation of mitochondrial calcium overload and amelioration of skeletal muscle atrophy. MFN2 attenuates sepsis-induced mitochondrial calcium overload through two complementary mechanisms: increasing ER-mitochondria distance and modulating GRP75-VDAC1 interaction and IP3R-GRP75-VDAC1 complex assembly. These findings identify MFN2 as a potential regulator of MAM-mediated mitochondrial calcium homeostasis in SIM and suggest it may represent a therapeutic target for sepsis-induced skeletal muscle dysfunction.

PMID 43010086
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PubMedZhonghua nan ke xue = National journal of andrology2026-11-11

[Therapeutic mechanism of Tiandan Qiyang Decoction in erectile dysfunction: An integrated approach combining network pharmacology, and molecular dynamics simulations].

Lu Yang Y, Wang Jian J, Wu Yancheng Y, Ye Siyuan S et al.

Objective The aim of this study is to investigate the underlying molecular mechanisms of Tiandan Qiyang Decoction (TDQYD) in treating erectile dysfunction (ED) and to provide insights for further research. Methods Integrated strategies including network pharmacology, molecular docking and molecular dynamics simulations were employed to explore the therapeutic mechanisms of TDQYD for ED. Results A total of 140 active ingredients, 1 143 associated target proteins, 513 highly relevant ED-related disease targets, and 176 potential therapeutic targets were identified. The core targets such as AKT1, ESR1/2, IL-6, IL-1B, EGFR, VEGFA, and PTGS2 were identified by PPI analysis. KEGG pathway enrichment analysis revealed that the formulation primarily regulates key signaling pathways, including AGE-RAGE, Prolactin, EGFR, HIF-1, Prostate cancer, Endocrine resistance, Serotonergic synapse, Lipid and atherosclerosis, etc. Network and Sankey diagram analyses highlighted the seven most prominent active compounds: isoliquiritigenin 4-methylether, Isoliquiritigenin, 3-deoxysappanchalcone, elenolide, micheliolide, bigelovin and 4-O-methylchinatin, while the most central core targets were EGFR, PTGS2, PIK3CA, GSK3B, and ESR1/2. Molecular docking simulations demonstrated strong binding affinities between the active components of TDQYD and the predicted therapeutic targets. Moreover, molecular dynamics simulations confirmed stable and robust interactions for the top-ranked complex pairs-ESR2_Bigelovin, ESR2_Micheliolide, EGFR_Isoliquiritigenin, and EGFR_4-O-Methylechinatin-across multiple evaluation metrics. The ELISA results demonstrated that the serum EGFR levels in the control group, pretreatment group, and posttreatment group were (244.12±57.16) pg/mL, (356.39±179.10) pg/mL and (263.01±122.08) pg/mL, respectively, showing a significant decrease after treatment (P<0.05). The corresponding serum ER levels were (93.39±70.61) ng/L, (47.44±11.97) ng/L and (69.65±48.67) ng/L, respectively, indicating a significant increase following treatment (P<0.01). Serum PTGS2 levels were measured as (3.55±1.58) ng/mL, (5.54±2.53) ng/mL and (3.84±1.61) ng/mL, respectively, and exhibited a significant reduction after treatment (P<0.05). GSH-Px levels were (46.07±15.27) pmol/mL, (31.55±5.37) pmol/mL and (39.13±11.97) pmol/mL, respectively, and showed a significant elevation posttreatment (P<0.01). Conclusion The core targets of TDQYD in the treatment of ED may be EGFR, PTGS2 and ER. This prescription acts on EGFR, HIF-1 and other pathways to improve ED by up-regulating ER, GSH-Px, and down-regulating EGFR, PTGS2 and other targets.

PMID 43012179
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