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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)
Want deeper analysis?Noah AI can explain complex mechanisms and compare to similar drugs.

Therapeutic Indications

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

Therapeutic AreaConditionPhase
Vascular disordersHypertension✓ Approved

Related Research Articles

PubMedArchives of toxicology2026-10-16

N-nitroso-hydrochlorothiazide: in vivo mutagenicity evaluation in a transgenic rodent model.

Ott Gregory R GR, Griffin Troy T, Bebb Kate K, Marinkovic Marina M et al.

N-nitrosamine drug substance related impurities (NDSRIs) are considered to be within the "cohort of concern" (CoC) due to their potential mutagenic carcinogenicity. However, increasing evidence indicates variability in mutagenic potency across this class. N-nitroso-hydrochlorothiazide (N-nitroso-HCTZ), an impurity associated with hydrochlorothiazide, has shown positive results in bacterial mutagenicity (Ames) assays, although mechanistic studies suggest these findings are likely driven by reactive degradation products rather than the parent compound. To further characterize mutagenic potential in vivo, a transgenic rodent (TGR) gene mutation assay was conducted in the Muta™Mouse test system. Male mice were administered N-nitroso-HCTZ by oral gavage at 0, 18.5, 55.7, 167, 500, or 750 mg/kg/day for 28 consecutive days. Mutant frequency (lacZ) was evaluated in liver and glandular stomach at 167, 500, and 750 mg/kg/day. Systemic exposure was confirmed in a toxicokinetic study following a single 750 mg/kg dose. N-nitroso-HCTZ was well tolerated, and no statistically significant increases in mutant frequency were observed in either tissue at any evaluated dose. All values were within historical control ranges, while the positive control demonstrated the anticipated response. Under the conditions of this study, N-nitroso-HCTZ did not induce gene mutations in vivo.

PMID 42881286
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PubMedCells2026-10-16

TRPs-NCX2 Axis Jointly Preserves Pancreatic Beta Cell Susceptibility/Sensitivity to Elevated Glucose.

Sagintayev Adlet A, Oflaz Furkan E FE, Kanlinuro Andra A, van Amsterdam Savina S et al.

Background: For appropriate glucose sensing, pancreatic beta-cells essentially establish a constant mitochondria-directed endoplasmic reticulum (ER) Ca2+ leak via phosphorylated presenilin-1 (PS1). In the current work, we investigated how cells maintain the ER Ca2+ content during this continuous Ca2+ leak. Methods: Ca2+ imaging for ER, cytosolic and subplasmalemmal Ca2+, high resolution respirometry, and ELISA for insulin secretion were used. Results: A novel ER Ca2+ refilling mechanism driven by reverse-mode NCX2, which is fueled by local Na+ influxes through TRPC3 and TRPV4 channels that are independent of STIM-ORAI1 was found in pancreatic rodent and human beta cell lines. Disrupting this TRPs-NCX2 axis reduces subplasmalemmal Ca2+ levels, abolishes glucose-induced cytosolic Ca2+ oscillations, suppresses glucose-triggered elevation in mitochondrial energetics, and impairs first-phase insulin secretion. Conclusions: We identified a novel, ORAI1-independent "TRPs-NCX2" relay that couples Na+ influx via TRPC3 and TRPV4 to NCX2 reverse mode to maintain ER Ca2+ stores during physiological basal ER Ca2+ leakage, which is fundamental to beta-cell responsiveness to elevated glucose.

PMID 42882464
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PubMedCells2026-10-16

Mitochondria-Endoplasmic Reticulum Crosstalk in Pancreatic β-Cell Stress: A Driver of Diabetes.

Niinuma Sara Anjum SA, Takemoto Ashleigh Suzu-Nishio AS, Khalil William Junior WJ, Butler Alexandra E AE et al.

Pancreatic β-cell failure is central to the pathogenesis of type 2 diabetes (T2D), developing when chronic metabolic stress overwhelms the adaptive capacity of these cells. Because insulin biosynthesis and glucose-stimulated secretion depend on tightly coordinated organelle function, crosstalk between the endoplasmic reticulum (ER) and mitochondria strongly influences β-cell fate. The two organelles are physically coupled at mitochondria-associated membranes (MAMs), contact sites that synchronize ER Ca2+ release with mitochondrial Ca2+ uptake and adenosine triphosphate (ATP) production, and that help regulate redox balance, autophagy, mitophagy and the unfolded protein response. This review draws together evidence on three questions. First, which stresses converge on the β-cell: ER stress, oxidative stress and dysregulated autophagy and mitophagy. Second, how ER-mitochondria crosstalk sustains β-cell health through Ca2+ handling and the proteins that maintain MAM integrity, including inositol 1,4,5-trisphosphate (IP3) receptors, voltage-dependent anion channel 1 (VDAC1), mitofusin 2 (Mfn2) and the ER stress sensors IRE1α and PERK. Third, how glucolipotoxic and inflammatory stress remodels these contacts and pushes communication towards a maladaptive state marked by mitochondrial Ca2+ overload, ROS accumulation, defective organelle quality control, cellular senescence and apoptosis. We contrast rodent and human data, where MAM composition and glucotoxic responses diverge, and consider therapeutic strategies, such as incretin-based agents and the mitochondrial-derived peptide MOTS-c, that target this interface to preserve β-cell function in diabetes.

PMID 42882431
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PubMedAnimals : an open access journal from MDPI2026-10-16

Chronic Energy Restriction Is Associated with Impaired Follicular Development and Hepatic Bile Acid Remodeling in Mice.

Zhu Wenjun W, Li Jiahao J, Cheng Xiaochan X, Zhang Hengyu H et al.

Chronic energy restriction (ER) can impair female reproductive function, but the peripheral metabolic mechanisms by which sustained energy deficiency disrupts follicular development remain poorly understood. This study aimed to determine whether hepatic bile acid (BA) remodeling contributes to the link between systemic energy availability and ovarian dysfunction. A chronic ER mouse model was established by reducing energy intake by 50% for 44 days. Multi-omics approaches, including hepatic transcriptomics, untargeted metabolomics, and targeted BA metabolomics, were integrated with ovarian functional analyses. ER significantly reduced ovarian weight, impaired follicular development, and decreased circulating concentrations of reproductive hormones. Hepatic transcriptomic and metabolomic analyses revealed extensive metabolic remodeling, with marked enrichment of BA-related pathways and increased expression of CYP7A1, suggesting increased hepatic BA synthetic capacity. Targeted BA profiling demonstrated elevated hepatic and circulating BA levels, including increased concentrations of several farnesoid X receptor (FXR)-activating BAs. Furthermore, ovarian FXR expression was increased, accompanied by decreased expression of key steroidogenic regulators, including SRB1, StAR, CYP11A1, and HSD3B1, consistent with reduced ovarian steroidogenic activity. These findings suggest that altered BA metabolism and increased ovarian FXR expression may contribute to reproductive dysfunction under chronic ER.

PMID 42882994
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PubMedInternational journal of molecular sciences2026-10-16

Diosgenin Alleviates Neuropathic Pain Associated with Alterations in Spinal Mitochondrial and ER Stress-Related Factors in CCI Mice.

Rahman Md Mahbubur MM, Yoon Taesu T, Yum Seung Hoon SH, Shim Ye Won YW et al.

Neuropathic pain is difficult to treat as current therapies are often insufficient and provide incomplete relief. However, the mechanisms of chronic nerve injury are poorly addressed. In the present study, we explored the therapeutic effects of natural steroidal saponin diosgenin and its possible spinal mechanisms in a mouse model of chronic constriction injury (CCI)-induced neuropathic pain. C57BL/6 mice underwent CCI and were orally administered diosgenin once daily from three days after surgery. Diosgenin significantly alleviated CCI-induced mechanical allodynia and thermal hyperalgesia and enhanced motor performance in paw withdrawal, open-field, and rotarod tests. These effects were associated with the restoration of mitochondrial homeostasis as evidenced by the increased mitochondrial fusion, decreased fission and activation of NRF2 signaling. Diosgenin also suppressed spinal endoplasmic reticulum (ER) stress, mitochondria apoptotic signaling and the expression of pro-inflammatory cytokines, and pain-related neuropeptides. Mechanistically, the inhibition of spinal NRF2 proteins and the pharmacological induction of ER stress reduced the analgesic effect of diosgenin, highlighting the critical involvement of these pathways in its therapeutic efficacy. Altogether, diosgenin alleviated neuropathic pain in CCI mice that were pharmacologically associated with the restoration of spinal mitochondrial function and ER stress suppression. Therefore, diosgenin could be a promising natural steroidal therapeutic candidate in alleviating neuropathic pain.

PMID 42883869
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PubMedBiology2026-10-16

Altered IRE1α-Dependent Decidual Programming Links Impaired Inflammation and Angiogenesis in Recurrent Implantation Failure.

Castagnola Lara L, Materazzi Lourdes L, Paparini Daniel D, Schafir Ana A et al.

Decidualization alters the endometrial stromal cells (EnSC) secretome, allowing sterile inflammation associated with embryo implantation, but mechanisms that lead to alterations in this process are still unknown. We evaluated whether impaired IRE1α-mediated endoplasmic reticulum (ER) stress signalling contributes to defective angiogenic decidual programming in patients with recurrent implantation failure (RIF). Candidate pathways were identified with bioinformatic analyses of endometrial arrays and validated in endometrial biopsies from fertile and RIF women (secretory phase) by RT-qPCR and in isolated EnSC by flow cytometry. Functional alterations were evaluated using trophoblast spheroid and endothelial cell migration assays. ER stress was pharmacologically induced in EnSC using thapsigargin. RIF endometria displayed impaired in vivo decidualization, with reduced expression of IGFBP1 and PGR, together with altered expression of molecules involved in blastocyst adhesion. Conditioned media from RIF-derived EnSC-impaired trophoblast outgrowth. RIF samples displayed an anti-angiogenic and altered inflammatory profile, characterized by reduced intracellular IL-1β accumulation, decreased VEGFA, and increased sFlt1 expression. Bioinformatic analyses identified IRE1α pathway as a central altered network associated with angiogenesis. Consistently, RIF samples showed reduced expression of IRE1α, sXBP1, and NLRP3. Moreover, ER stress induction in EnSC promoted endothelial cell migration. RIF is associated with defective angiogenic decidual programming linked to impaired IRE1α-mediated ER stress signalling. These findings identify the IRE1α axis as a potential pathway of interest for future therapeutic exploration in recurrent implantation failure.

PMID 42883366
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