{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:49:30Z","timestamp":1786121370987,"version":"build-2736575974"},"reference-count":72,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Fonds de la Recherche Scientifique de Belgique","award":["353230060"],"award-info":[{"award-number":["353230060"]}]},{"name":"Fonds de la Recherche Scientifique de Belgique","award":["40002303"],"award-info":[{"award-number":["40002303"]}]},{"award":["353230060"],"award-info":[{"award-number":["353230060"]}],"id":[{"id":"https:\/\/ror.org\/03q83t159","id-type":"ROR","asserted-by":"publisher"}]},{"award":["40002303"],"award-info":[{"award-number":["40002303"]}],"id":[{"id":"https:\/\/ror.org\/03q83t159","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002910","name":"F\u00e9d\u00e9ration Wallonie-Bruxelles","doi-asserted-by":"crossref","award":["ARC 21\/25-08"],"award-info":[{"award-number":["ARC 21\/25-08"]}],"id":[{"id":"10.13039\/501100002910","id-type":"DOI","asserted-by":"crossref"}]},{"award":["ARC 21\/25-08"],"award-info":[{"award-number":["ARC 21\/25-08"]}],"id":[{"id":"https:\/\/ror.org\/04q01pf08","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Molecules"],"abstract":"<jats:p>Our previous study demonstrated that bis-(1,2,3,4-tetrahydroisoquinoline) (bis-THIQ) compounds such as tetrandrine and AG525E1 exhibit significant affinity for SK channels. Interestingly, the stereoisomers of AG525 display markedly different affinities toward SK channels, with the (S,S) stereoisomer being the best ligand. Previous structure-based in silico investigations failed to provide a satisfactory explanation for these differences. Moreover, a series of simplified THIQ derivatives derived from AG525 showed little or no affinity for SK channels, raising questions about the structural features required for binding to SK channels. To better understand the structure\u2013activity relationships within this chemical family with diverse three-dimensional features, a ligand-based approach is developed in this work. Using a dataset composed of AG525 stereoisomers and natural bis-THIQ derivatives, a pharmacophore model was generated to identify key molecular features required for binding to SK channels and to rationalize the observed differences in activity. Twenty pharmacophore hypotheses were generated, with the best-ranked models highlighting five major interaction features: an aromatic ring, one acceptor group associated with this ring, one lipophilic feature, one positive charge, and a second acceptor site located farther from the THIQ moiety. This model differs from previously proposed pharmacophores emphasizing the presence of two positive charges. Two alkaloids recently identified as SK channel ligands, (1) and (2), were found to match all five pharmacophoric features despite not being included in the training set. The absence of SK affinity of a series of simplified THIQ analogues derived from AG525 could be explained using the model. To go further, the predictive value of the model was evaluated by evaluating in silico the propensity of a series of cyclic and non-cyclic bis-THIQ alkaloids to bind to SK channels. High fitting scores were obtained for these compounds, and subsequent in vitro experiments, using radioligand competitive binding assays, were performed and confirmed that they belong as ligands.<\/jats:p>","DOI":"10.3390\/molecules31152723","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T13:16:29Z","timestamp":1785935789000},"page":"2723","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Further Investigations on Natural and Synthetic Bis-(1,2,3,4-tetrahydroisoquinoline) Derivatives Interacting with the Apamin-Sensitive Site of Small-Conductance Calcium-Activated Potassium Channels"],"prefix":"10.3390","volume":"31","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-6286-9091","authenticated-orcid":false,"given":"Hossein","family":"Taouba","sequence":"first","affiliation":[{"name":"Laboratory of Medicinal Chemistry, Center for Interdisciplinary Research on Medicines (CIRM), University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4027-5207","authenticated-orcid":false,"given":"Romain","family":"Vitello","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemistry, Center for Interdisciplinary Research on Medicines (CIRM), University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Donna","family":"Pereira Barbon","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemistry, Center for Interdisciplinary Research on Medicines (CIRM), University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0000-3370-9153","authenticated-orcid":false,"given":"Jean-Luc","family":"Hayen","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemistry, Center for Interdisciplinary Research on Medicines (CIRM), University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-9304-1118","authenticated-orcid":false,"given":"Coralie","family":"Herbet","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemistry, Center for Interdisciplinary Research on Medicines (CIRM), University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Szymon Piotr","family":"Fali\u0144ski","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemistry, Center for Interdisciplinary Research on Medicines (CIRM), University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6898-9036","authenticated-orcid":false,"given":"Nikolay","family":"Tumanov","sequence":"additional","affiliation":[{"name":"Namur Institute of Structured Matter (NISM) and Namur Research Institute for Life Sciences (NARILIS) Research Institutes, Department of Chemistry, University of Namur, 5000 Namur, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4920-6857","authenticated-orcid":false,"given":"Johan","family":"Wouters","sequence":"additional","affiliation":[{"name":"Namur Institute of Structured Matter (NISM) and Namur Research Institute for Life Sciences (NARILIS) Research Institutes, Department of Chemistry, University of Namur, 5000 Namur, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Fran\u00e7ois","family":"Li\u00e9geois","sequence":"additional","affiliation":[{"name":"Laboratory of Medicinal Chemistry, Center for Interdisciplinary Research on Medicines (CIRM), University of Li\u00e8ge, 4000 Li\u00e8ge, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"152956","DOI":"10.1016\/j.phymed.2019.152956","article-title":"Cepharanthine: An update of its mode of action, pharmacological properties and medical applications","volume":"62","author":"Bailly","year":"2019","journal-title":"Phytomedicine"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"118051","DOI":"10.1016\/j.bmc.2024.118051","article-title":"Targeting glioma with heteroaromatic alkaloids: A review of potential therapeutics","volume":"121","author":"Ichikawa","year":"2025","journal-title":"Bioorg. Med. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1021\/acsmedchemlett.3c00452","article-title":"The Bis(1,2,3,4-tetrahydroisoquinoline) Alkaloids Cepharanthine and Berbamine Are Ligands of SK Channels","volume":"15","author":"Vitello","year":"2024","journal-title":"ACS Med. Chem. Lett."},{"key":"ref_4","unstructured":"Vitello, R. (2025). Towards Better SK Tools: Improving the SK Pharmacophore Model. [Ph.D. Thesis, University of Li\u00e8ge]."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"41404","DOI":"10.1074\/jbc.M509610200","article-title":"Specific enhancement of SK channel activity selectively potentiates the afterhyperpolarizing current I(AHP) and modulates the firing properties of hippocampal pyramidal neurons","volume":"280","author":"Pedarzani","year":"2005","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1161\/CIRCEP.110.957407","article-title":"Inhibition of small-conductance Ca2+-activated K+ channels terminates and protects against atrial fibrillation","volume":"3","author":"Diness","year":"2010","journal-title":"Circ. Arrhythmia Electrophysiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1038\/sj.bjp.0702467","article-title":"Effect of potassium channel modulators in mouse forced swimming test","volume":"126","author":"Galeotti","year":"1999","journal-title":"Br. J. Pharmacol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"e21416","DOI":"10.7554\/eLife.21416","article-title":"Chronic social isolation reduces 5-HT neuronal activity via upregulated SK3 calcium-activated potassium channels","volume":"5","author":"Sargin","year":"2016","journal-title":"eLife"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"4852","DOI":"10.1158\/0008-5472.CAN-12-4572","article-title":"Pivotal Role of the Lipid Raft SK3\u2013Orai1 Complex in Human Cancer Cell Migration and Bone Metastases","volume":"73","author":"Clarysse","year":"2013","journal-title":"Cancer Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1853","DOI":"10.1002\/1878-0261.13631","article-title":"Plasma membrane SK2 channel activity regulates migration and chemosensitivity of high-grade serous ovarian cancer cells","volume":"18","author":"Romito","year":"2024","journal-title":"Mol. Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1113\/jphysiol.2005.096818","article-title":"Ca2+-activated K+ channels in human melanoma cells are up-regulated by hypoxia involving hypoxia-inducible factor-1\u03b1 and the von Hippel-Lindau protein","volume":"571","author":"Tajima","year":"2006","journal-title":"J. Physiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2946","DOI":"10.1158\/1535-7163.MCT-06-0194","article-title":"Identification of SK3 channel as a new mediator of breast cancer cell migration","volume":"5","author":"Potier","year":"2006","journal-title":"Mol. Cancer Ther."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1770","DOI":"10.1038\/s41467-026-68475-4","article-title":"Structural mechanisms for inhibition and activation of human small-conductance Ca2+-activated potassium channel SK2","volume":"17","author":"Ma","year":"2026","journal-title":"Nat. Commun."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Diness, J.G., Kirchhoff, J.E., Speerschneider, T., Abildgaard, L., Edvardsson, N., S\u00f8rensen, U.S., Grunnet, M., and Bentzen, B.H. (2020). The KCa2 Channel Inhibitor AP30663 Selectively Increases Atrial Refractoriness, Converts Vernakalant-Resistant Atrial Fibrillation and Prevents Its Reinduction in Conscious Pigs. Front. Pharmacol., 11.","DOI":"10.3389\/fphar.2020.00159"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1111\/bcp.15973","article-title":"A phase 1 trial of AP30663, a KCa 2 channel inhibitor in development for conversion of atrial fibrillation","volume":"90","author":"Yfanti","year":"2024","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/s41591-023-02679-9","article-title":"Inhibition of the KCa2 potassium channel in atrial fibrillation: A randomized phase 2 trial","volume":"30","author":"Holst","year":"2024","journal-title":"Nat. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1308","DOI":"10.1073\/pnas.79.4.1308","article-title":"Apamin as a selective blocker of the calcium-dependent potassium channel in neuroblastoma cells: Voltage-clamp and biochemical characterization of the toxin receptor","volume":"79","author":"Hugues","year":"1982","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"718","DOI":"10.1038\/323718a0","article-title":"Single apamin-blocked Ca-activated K+ channels of small conductance in cultured rat skeletal muscle","volume":"323","author":"Blatz","year":"1986","journal-title":"Nature"},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Kuzmenkov, A.I., Peigneur, S., Nasburg, J.A., Mineev, K.S., Nikolaev, M.V., Pinheiro-Junior, E.L., Arseniev, A.S., Wulff, H., Tytgat, J., and Vassilevski, A.A. (2022). Apamin structure and pharmacology revisited. Front. Pharmacol., 13.","DOI":"10.3389\/fphar.2022.977440"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/0014-5793(68)80033-X","article-title":"The disulphide bridges of apamin","volume":"1","author":"Callewaert","year":"1968","journal-title":"FEBS Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"15944","DOI":"10.1021\/bi002044q","article-title":"The Asparagine-Stabilized \u03b2-Turn of Apamin: Contribution to Structural Stability from Dynamics Simulation and Amide Hydrogen Exchange Analysis","volume":"39","author":"Dempsey","year":"2000","journal-title":"Biochemistry"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"27067","DOI":"10.1074\/jbc.M110.110072","article-title":"Allosteric Block of KCa2 Channels by Apamin*","volume":"285","author":"Lamy","year":"2010","journal-title":"J. Biol. Chem."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"18494","DOI":"10.1073\/pnas.1110724108","article-title":"Crucial role of a shared extracellular loop in apamin sensitivity and maintenance of pore shape of small-conductance calcium-activated potassium (SK) channels","volume":"108","author":"Weatherall","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"3690","DOI":"10.1038\/s41467-025-59061-1","article-title":"Cryo-EM structures of the small-conductance Ca2+-activated KCa2.2 channel","volume":"16","author":"Nam","year":"2025","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"RP107733","DOI":"10.7554\/eLife.107733.3","article-title":"Mechanism of SK2 channel gating and its modulation by the bee toxin apamin and small molecules","volume":"14","author":"Cassell","year":"2025","journal-title":"eLife"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/S0028-3908(01)00067-3","article-title":"Characterisation of [125I] -apamin binding sites in rat brain membranes and HEK293 cells transfected with SK channel subtypes","volume":"41","author":"Finlayson","year":"2001","journal-title":"Neuropharmacology"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1201","DOI":"10.1016\/j.bmc.2004.11.025","article-title":"Synthesis and biological evaluation of N-methyl-laudanosine iodide analogues as potential SK channel blockers","volume":"13","author":"Graulich","year":"2005","journal-title":"Bioorg. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1002\/anie.201508445","article-title":"MiniAp-4: A Venom-Inspired Peptidomimetic for Brain Delivery","volume":"55","author":"Ciudad","year":"2016","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1016\/j.pneurobio.2008.12.002","article-title":"Delivery of peptide and protein drugs over the blood\u2013brain barrier","volume":"87","author":"Brasnjevic","year":"2009","journal-title":"Prog. Neurobiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1111\/cbdd.12055","article-title":"The Future of Peptide-based Drugs","volume":"81","author":"Craik","year":"2013","journal-title":"Chem. Biol. Drug Des."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1021\/jm970571a","article-title":"Bis-Quinolinium Cyclophanes:\u2009 6,10-Diaza-3(1,3),8(1,4)-dibenzena-1,5(1,4)- diquinolinacyclodecaphane (UCL 1684), the First Nanomolar, Non-Peptidic Blocker of the Apamin-Sensitive Ca2+-Activated K+ Channel","volume":"41","author":"Rosa","year":"1998","journal-title":"J. Med. Chem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1653","DOI":"10.1016\/S0028-3908(97)00147-0","article-title":"Evidence for a non-GABAergic action of quaternary salts of bicuculline on dopaminergic neurones","volume":"36","author":"Seutin","year":"1997","journal-title":"Neuropharmacology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1176","DOI":"10.1124\/jpet.302.3.1176","article-title":"Methyl-Laudanosine: A New Pharmacological Tool to Investigate the Function of Small-Conductance Ca2+-Activated K+Channels","volume":"302","author":"Massotte","year":"2002","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"3440","DOI":"10.1016\/j.bmcl.2008.03.069","article-title":"Bis-tetrahydroisoquinoline derivatives: AG525E1, a new step in the search for non-quaternary non-peptidic small conductance Ca2+-activated K+ channel blockers","volume":"18","author":"Graulich","year":"2008","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1002\/cmdc.201400028","article-title":"Bis-(1,2,3,4-tetrahydroisoquinolinium): A Chiral Scaffold for Developing High-Affinity Ligands for SK Channels","volume":"9","author":"Wouters","year":"2014","journal-title":"ChemMedChem"},{"key":"ref_36","unstructured":"Phillips, P.E.M., Sandberg, S.G., Ahn, S., and Phillips, A.G. (2008). The SK channel blocker AG525E1 increases locomotor activity and in vivo dopamine release in the rat nucleus accumbens. Monitoring Molecules in Neuroscience\u2014Proceedings of the 12th International Conference on In Vivo Methods, University of British Columbia."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Tighilet, B., Bourdet, A., P\u00e9ricat, D., Timon-David, E., Rastoldo, G., and Chabbert, C. (2021). SK Channels Modulation Accelerates Equilibrium Recovery in Unilateral Vestibular Neurectomized Rats. Pharmaceuticals, 14.","DOI":"10.3390\/ph14121226"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"517","DOI":"10.1080\/14756360500210989","article-title":"Identification of a pharmacophore of SKCa channel blockers","volume":"20","author":"Dilly","year":"2005","journal-title":"J. Enzym. Inhib. Med. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"5070","DOI":"10.1021\/jm070412j","article-title":"Synthesis and Radioligand Binding Studies of Bis-isoquinolinium Derivatives as Small Conductance Ca2+-Activated K+ Channel Blockers","volume":"50","author":"Graulich","year":"2007","journal-title":"J. Med. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4972","DOI":"10.1021\/jm049025p","article-title":"Synthesis and radioligand binding studies of C-5- and C-8-Substituted 1-(3,4-Dimethoxybenzyl)-2,2-dimethyl-1,2,3,4-tetrahydroisoquinoliniums as SK channel blockers related to N-Methyl-laudanosine and N-Methyl-noscapine","volume":"48","author":"Graulich","year":"2005","journal-title":"J. Med. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"7208","DOI":"10.1021\/jm0607395","article-title":"Synthesis and Radioligand Binding Studies of Methoxylated 1,2,3,4-Tetrahydroisoquinolinium Derivatives as Ligands of the Apamin-Sensitive Ca2+-Activated K+ Channels","volume":"49","author":"Graulich","year":"2006","journal-title":"J. Med. Chem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3240","DOI":"10.1016\/j.ejmech.2010.03.020","article-title":"Bis-tetrahydroisoquinoline derivatives: Structure analysis of the three stereoisomers of 1,1\u2032-(propane-1,3-diyl)-bis-(6,7-dimethoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline)","volume":"45","author":"Wouters","year":"2010","journal-title":"Eur. J. Med. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"117237","DOI":"10.1016\/j.lfs.2019.117237","article-title":"Antioxidative and antiapoptosis: Neuroprotective effects of dauricine in Alzheimer\u2019s disease models","volume":"243","author":"Wang","year":"2020","journal-title":"Life Sci."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Park, H.-J., Gholam Zadeh, M., Suh, J.-H., and Choi, H.-S. (2020). Dauricine Protects from LPS-Induced Bone Loss via the ROS\/PP2A\/NF-\u03baB Axis in Osteoclasts. Antioxidants, 9.","DOI":"10.3390\/antiox9070588"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1016\/j.abb.2019.03.018","article-title":"Dauricine negatively regulates lipopolysaccharide- or cecal ligation and puncture-induced inflammatory response via NF-\u03baB inactivation","volume":"666","author":"Qiao","year":"2019","journal-title":"Arch. Biochem. Biophys."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"477","DOI":"10.1142\/S0192415X07004990","article-title":"Inhibitory Effect of Dauricine on Inflammatory Process Following Focal Cerebral Ischemia\/Reperfusion in Rats","volume":"35","author":"Yang","year":"2007","journal-title":"Am. J. Chin. Med."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"266","DOI":"10.1002\/jcp.22261","article-title":"Dauricine induces apoptosis, inhibits proliferation and invasion through inhibiting NF-\u03baB signaling pathway in colon cancer cells","volume":"225","author":"Yang","year":"2010","journal-title":"J. Cell. Physiol."},{"key":"ref_48","doi-asserted-by":"crossref","unstructured":"Liu, Y., Wang, C., Liao, Q., and Du, C. (2025). Pharmacological Potential and Mechanisms of Bisbenzylisoquinoline Alkaloids from Lotus Seed Embryos. Biomolecules, 15.","DOI":"10.3390\/biom15101377"},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Kadioglu, O., Law, B.Y.K., Mok, S.W.F., Xu, S.-W., Efferth, T., and Wong, V.K.W. (2017). Mode of Action Analyses of Neferine, a Bisbenzylisoquinoline Alkaloid of Lotus (Nelumbo nucifera) against Multidrug-Resistant Tumor Cells. Front. Pharmacol., 8.","DOI":"10.3389\/fphar.2017.00238"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"110652","DOI":"10.1016\/j.fct.2019.110652","article-title":"Neferine and isoliensinine enhance \u2018intracellular uptake of cisplatin\u2019 and induce \u2018ROS-mediated apoptosis\u2019 in colorectal cancer cells\u2014A comparative study","volume":"132","author":"Manogaran","year":"2019","journal-title":"Food Chem. Toxicol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"177393","DOI":"10.1016\/j.ejphar.2025.177393","article-title":"Neferine attenuates hypertensive cardiomyocyte apoptosis and modulates key signaling pathways: An in vivo and in vitro study","volume":"994","author":"Guo","year":"2025","journal-title":"Eur. J. Pharmacol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Cheng, Y., Li, H.-L., Zhou, Z.-W., Long, H.-Z., Luo, H.-Y., Wen, D.-D., Cheng, L., and Gao, L.-C. (2021). Isoliensinine: A Natural Compound with \u201cDrug-Like\u201d Potential. Front. Pharmacol., 12.","DOI":"10.3389\/fphar.2021.630385"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Jung, Y.Y., Shanmugam, M.K., Chinnathambi, A., Alharbi, S.A., Shair, O.H.M., Um, J.-Y., Sethi, G., and Ahn, K.S. (2019). Fangchinoline, a Bisbenzylisoquinoline Alkaloid can Modulate Cytokine-Impelled Apoptosis via the Dual Regulation of NF-\u03baB and AP-1 Pathways. Molecules, 24.","DOI":"10.3390\/molecules24173127"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1790","DOI":"10.1002\/ptr.4936","article-title":"Fangchinoline Induces G1 Arrest in Breast Cancer Cells Through Cell-Cycle Regulation","volume":"27","author":"Xing","year":"2013","journal-title":"Phytother. Res."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"4066","DOI":"10.1021\/acsinfecdis.4c00600","article-title":"Fangchinoline Inhibits Zika Virus by Disrupting Virus Internalization","volume":"10","author":"Yang","year":"2024","journal-title":"ACS Infect. Dis."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1111\/j.1472-8206.1998.tb00939.x","article-title":"Calcium antagonist properties of the bisbenzylisoquinoline alkaloid cycleanine","volume":"12","author":"Bello","year":"1998","journal-title":"Fundam. Clin. Pharmacol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1007\/s00894-022-05326-1","article-title":"The impact of cycleanine in cancer research: A computational study","volume":"28","author":"Nwaefulu","year":"2022","journal-title":"J. Mol. Model."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e01995-20","DOI":"10.1128\/AAC.01995-20","article-title":"In Vivo Efficacy and Metabolism of the Antimalarial Cycleanine and Improved In Vitro Antiplasmodial Activity of Semisynthetic Analogues","volume":"65","author":"Uche","year":"2021","journal-title":"Antimicrob. Agents Chemother."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"4231","DOI":"10.1016\/j.bmcl.2004.06.011","article-title":"Bis-quinolinium cyclophanes: Toward a pharmacophore model for the blockade of apamin-sensitive SKCa channels in sympathetic neurons","volume":"14","author":"Galanakis","year":"2004","journal-title":"Bioorg. Med. Chem. Lett."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1021\/np50001a001","article-title":"Bisbenzylisoquinoline Alkaloids\u2014A Review","volume":"42","author":"Guha","year":"1979","journal-title":"J. Nat. Prod."},{"key":"ref_61","unstructured":"Shamma, M. (1972). The bisbenzylisoquinoline alkaloids. The Isoquinoline Alkaloids: Chemistry and Pharmacology, Academic Press."},{"key":"ref_62","first-page":"1","article-title":"The Bisbenzylisoquinoline Alkaloids\u2014A Tabular Review","volume":"Volume 14","author":"Schiff","year":"1999","journal-title":"Alkaloids: Chemical and Biological Perspectives"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"104517","DOI":"10.1016\/j.bioorg.2020.104517","article-title":"Analgesic bisbenzylisoquinoline alkaloids from the rhizoma of Menispermum dauricum DC","volume":"107","author":"Wei","year":"2021","journal-title":"Bioorg. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"3047","DOI":"10.1039\/D0OB00078G","article-title":"A modular approach to the bisbenzylisoquinoline alkaloids tetrandrine and isotetrandrine","volume":"18","author":"Meixner","year":"2020","journal-title":"Org. Biomol. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1038\/sj.bjp.0703111","article-title":"The pharmacology of hSK1 Ca2+-activated K+ channels expressed in mammalian cell lines","volume":"129","author":"Shah","year":"2000","journal-title":"Br. J. Pharmacol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1016\/0014-2999(93)90590-E","article-title":"Dequalinium: A potent inhibitor of apamin-sensitive K+ channels in hepatocytes and of nicotinic responses in skeletal muscle","volume":"236","author":"Castle","year":"1993","journal-title":"Eur. J. Pharmacol."},{"key":"ref_67","first-page":"1","article-title":"Bisbenzylisoquinoline Alkaloids","volume":"Volume 81","author":"Weber","year":"2019","journal-title":"The Alkaloids: Chemistry and Biology"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1021\/np50052a001","article-title":"Bisbenzylisoquinoline Alkaloids","volume":"50","author":"Schiff","year":"1987","journal-title":"J. Nat. Prod."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"23195","DOI":"10.1074\/jbc.272.37.23195","article-title":"Determinants of Apamin and d-Tubocurarine Block in SK Potassium Channels","volume":"272","author":"Ishii","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"625","DOI":"10.2174\/0929867033457908","article-title":"Modulation of Small Conductance Calcium-Activated Potassium (SK) Channels: A New Challenge in Medicinal Chemistry","volume":"10","author":"Mercier","year":"2003","journal-title":"Curr. Med. Chem."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"3099","DOI":"10.1016\/0006-2952(73)90196-2","article-title":"Relationship between the inhibition constant (&) and the concentration of inhibitor which causes 50 percent inhibition (Iso) of an enzymatic reaction","volume":"22","author":"Cheng","year":"1973","journal-title":"Biochem. Pharmacol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1111\/j.1747-0285.2006.00384.x","article-title":"PHASE: A Novel Approach to Pharmacophore Modeling and 3D Database Searching","volume":"67","author":"Dixon","year":"2006","journal-title":"Chem. Biol. Drug Des."}],"container-title":["Molecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/15\/2723\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T04:32:37Z","timestamp":1786077157000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1420-3049\/31\/15\/2723"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,5]]},"references-count":72,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["molecules31152723"],"URL":"https:\/\/doi.org\/10.3390\/molecules31152723","relation":{},"ISSN":["1420-3049"],"issn-type":[{"value":"1420-3049","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,5]]}}}