Molecular Pharmacology最新文献

{"title":"Extrahelical Binding Site for a 1<i>H</i>-Imidazo[4,5-c]quinolin-4-amine A₃ Adenosine Receptor Positive Allosteric Modulator on Helix 8 and Distal Portions of Transmembrane Domains 1 and 7.","authors":"Courtney L Fisher, Matteo Pavan, Veronica Salmaso, Robert F Keyes, Tina C Wan, Balaram Pradhan, Zhan-Guo Gao, Brian C Smith, Kenneth A Jacobson, John A Auchampach","doi":"10.1124/molpharm.123.000784","DOIUrl":"10.1124/molpharm.123.000784","url":null,"abstract":"<p><p>This study describes the localization and computational prediction of a binding site for the A₃ adenosine receptor (A₃AR) positive allosteric modulator 2-cyclohexyl-1<i>H</i>-imidazo[4,5-c]quinolin-4-(3,4-dichlorophenyl)amine (LUF6000). The work reveals an extrahelical lipid-facing binding pocket disparate from the orthosteric binding site that encompasses transmembrane domain (TMD) 1, TMD7, and Helix (H) 8, which was predicted by molecular modeling and validated by mutagenesis. According to the model, the nearly planar 1<i>H</i>-imidazo[4,5-c]quinolinamine ring system lies parallel to the transmembrane segments, inserted into an aromatic cage formed by π-π stacking interactions with the side chains of Y284^7.55 in TMD7 and Y293^8.54 in H8 and by π-NH bonding between Y284^7.55 and the exocyclic amine. The 2-cyclohexyl group is positioned \"upward\" within a small hydrophobic subpocket created by residues in TMDs 1 and 7, while the 3,4-dichlorophenyl group extends toward the lipid interface. An H-bond between the N<i>-</i>1 amine of the heterocycle and the carbonyl of G29^1.49 further stabilizes the interaction. Molecular dynamics simulations predicted two metastable intermediates, one resembling a pose determined by molecular docking and a second involving transient interactions with Y293^8.54; in simulations, each of these intermediates converges into the final bound state. Structure-activity-relationships for replacement of either of the identified exocyclic or endocyclic amines with heteroatoms lacking H-bond donating ability were consistent with the hypothetical pose. Thus, we characterized an allosteric pocket for 1<i>H</i>-imidazo[4,5-c]quinolin-4-amines that is consistent with data generated by orthogonal methods, which will aid in the rational design of improved A₃AR positive allosteric modulators. SIGNIFICANCE STATEMENT: Orthosteric A₃AR agonists have advanced in clinical trials for inflammatory conditions, liver diseases, and cancer. Thus, the clinical appeal of selective receptor activation could extend to allosteric enhancers, which would induce site- and time-specific activation in the affected tissue. By identifying the allosteric site for known positive allosteric modulators, structure-based drug discovery modalities can be enabled to enhance the pharmacological properties of the 1<i>H</i>-imidazo[4,5-c]quinolin-4-amine class of A₃AR positive allosteric modulators.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":" ","pages":"213-223"},"PeriodicalIF":3.2,"publicationDate":"2024-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10877738/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139106399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Perspective: Therapeutic Implications for Sphingolipids in Health and Disease.","authors":"Christopher J Clarke, Ashley J Snider","doi":"10.1124/molpharm.124.000866","DOIUrl":"10.1124/molpharm.124.000866","url":null,"abstract":"<p><p>Long thought to be structural components of cell membranes, sphingolipids (SLs) have emerged as bioactive molecules whose metabolism is tightly regulated. These bioactive lipids and their metabolic enzymes have been implicated in numerous disease states, including lysosomal storage disorders, multiple sclerosis, inflammation, and cancer as well as metabolic syndrome and obesity. In addition, the indications for many of these lipids to potentially serve as biomarkers for disease continue to emerge with increasing metabolomic and lipidomic studies. The implications of these studies have, in turn, led to the examination of SL enzymes and their bioactive lipids as potential therapeutic targets and as markers for therapeutic efficacy. SIGNIFICANCE STATEMENT: Many sphingolipids (SLs) and their metabolizing enzymes have been implicated in disease. This perspective highlights the potential for SLs to serve as therapeutic targets and diagnostic markers and discusses the implications for the studies and reviews highlighted in this Special Section on Therapeutic Implications for Sphingolipids in Health and Disease.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"105 3","pages":"118-120"},"PeriodicalIF":3.2,"publicationDate":"2024-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139741495","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacologic Characterization of LTGO-33, a Selective Small Molecule Inhibitor of the Voltage-Gated Sodium Channel Na_V1.8 with a Unique Mechanism of Action.","authors":"John M Gilchrist, Nien-Du Yang, Victoria Jiang, Bryan D Moyer","doi":"10.1124/molpharm.123.000789","DOIUrl":"10.1124/molpharm.123.000789","url":null,"abstract":"<p><p>Discovery and development of new molecules directed against validated pain targets is required to advance the treatment of pain disorders. Voltage-gated sodium channels (Na_Vs) are responsible for action potential initiation and transmission of pain signals. Na_V1.8 is specifically expressed in peripheral nociceptors and has been genetically and pharmacologically validated as a human pain target. Selective inhibition of Na_V1.8 can ameliorate pain while minimizing effects on other Na_V isoforms essential for cardiac, respiratory, and central nervous system physiology. Here we present the pharmacology, interaction site, and mechanism of action of LTGO-33, a novel Na_V1.8 small molecule inhibitor. LTGO-33 inhibited Na_V1.8 in the nM potency range and exhibited over 600-fold selectivity against human Na_V1.1-Na_V1.7 and Na_V1.9. Unlike prior reported Na_V1.8 inhibitors that preferentially interacted with an inactivated state via the pore region, LTGO-33 was state-independent with similar potencies against closed and inactivated channels. LTGO-33 displayed species specificity for primate Na_V1.8 over dog and rodent Na_V1.8 and inhibited action potential firing in human dorsal root ganglia neurons. Using chimeras combined with mutagenesis, the extracellular cleft of the second voltage-sensing domain was identified as the key site required for channel inhibition. Biophysical mechanism of action studies demonstrated that LTGO-33 inhibition was relieved by membrane depolarization, suggesting the molecule stabilized the deactivated state to prevent channel opening. LTGO-33 equally inhibited wild-type and multiple Na_V1.8 variants associated with human pain disorders. These collective results illustrate LTGO-33 inhibition via both a novel interaction site and mechanism of action previously undescribed in Na_V1.8 small molecule pharmacologic space. SIGNIFICANCE STATEMENT: Na_V1.8 sodium channels primarily expressed in peripheral pain-sensing neurons represent a validated target for the development of novel analgesics. Here we present the selective small molecule Na_V1.8 inhibitor LTGO-33 that interdicts a distinct site in a voltage-sensor domain to inhibit channel opening. These results inform the development of new analgesics for pain disorders.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":" ","pages":"233-249"},"PeriodicalIF":3.2,"publicationDate":"2024-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139403662","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>ent</i>-Verticilide B1 Inhibits Type 2 Ryanodine Receptor Channels and is Antiarrhythmic in <i>Casq2</i> ^-/- Mice.","authors":"Aaron Gochman, Tri Q Do, Kyungsoo Kim, Jacob A Schwarz, Madelaine P Thorpe, Daniel J Blackwell, Paxton A Ritschel, Abigail N Smith, Robyn T Rebbeck, Wendell S Akers, Razvan L Cornea, Derek R Laver, Jeffrey N Johnston, Bjorn C Knollmann","doi":"10.1124/molpharm.123.000752","DOIUrl":"10.1124/molpharm.123.000752","url":null,"abstract":"<p><p>Intracellular Ca²⁺ leak from cardiac ryanodine receptor (RyR2) is an established mechanism of sudden cardiac death (SCD), whereby dysregulated Ca²⁺ handling causes ventricular arrhythmias. We previously discovered the RyR2-selective inhibitor <i>ent-</i>(+)-verticilide (<i>ent</i>-1), a 24-membered cyclooligomeric depsipeptide that is the enantiomeric form of a natural product (<i>nat</i>-(-)-verticilide). Here, we examined its 18-membered ring-size oligomer (<i>ent</i>-verticilide B1; \"<i>ent</i>-B1\") in RyR2 single channel and [³H]ryanodine binding assays, and in <i>Casq2</i> ^-/- cardiomyocytes and mice, a gene-targeted model of SCD. <i>ent</i>-B1 inhibited RyR2 single channels and RyR2-mediated spontaneous Ca²⁺ release in <i>Casq2</i> ^-/- cardiomyocytes with sub-micromolar potency. <i>ent</i>-B1 was a partial RyR2 inhibitor, with maximal inhibitory efficacy of less than 50%. <i>ent</i>-B1 was stable in plasma, with a peak plasma concentration of 1460 ng/ml at 10 minutes and half-life of 45 minutes after intraperitoneal administration of 3 mg/kg in mice. In vivo, <i>ent</i>-B1 significantly reduced catecholamine-induced ventricular arrhythmias in <i>Casq2</i> ^-/- mice in a dose-dependent manner. Hence, we have identified a novel chemical entity - <i>ent</i>-B1 - that preserves the mechanism of action of a hit compound and shows therapeutic efficacy. These findings strengthen RyR2 as an antiarrhythmic drug target and highlight the potential of investigating the mirror-image isomers of natural products to discover new therapeutics. SIGNIFICANCE STATEMENT: The cardiac ryanodine receptor (RyR2) is an untapped target in the stagnant field of antiarrhythmic drug development. We have confirmed RyR2 as an antiarrhythmic target in a mouse model of sudden cardiac death and shown the therapeutic efficacy of a second enantiomeric natural product.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":" ","pages":"194-201"},"PeriodicalIF":3.2,"publicationDate":"2024-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10877729/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139521396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Brief Overview of the Toxic Sphingomyelinase Ds of Brown Recluse Spider Venom and Other Organisms and Simple Methods To Detect Production of Its Signature Cyclic Ceramide Phosphate.","authors":"Hannah Lachmayr, Alfred H Merrill","doi":"10.1124/molpharm.123.000709","DOIUrl":"10.1124/molpharm.123.000709","url":null,"abstract":"<p><p>A special category of phospholipase D (PLD) in the venom of the brown recluse spider (<i>Loxosceles reclusa</i>) and several other sicariid spiders accounts for the dermonecrosis and many of the other clinical symptoms of envenomation. Related proteins are produced by other organisms, including fungi and bacteria. These PLDs are often referred to as sphingomyelinase Ds (SMase Ds) because they cleave sphingomyelin (SM) to choline and \"ceramide phosphate.\" The lipid product has actually been found to be a novel sphingolipid: ceramide 1,3-cyclic phosphate (Cer1,3P). Since there are no effective treatments for the injury induced by the bites of these spiders, SMase D/PLDs are attractive targets for therapeutic intervention, and some of their features will be described in this minireview. In addition, two simple methods are described for detecting the characteristic SMase D activity using a fluorescent SM analog, (N-[12-[(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]dodecanoyl]-SM (C12-NBD-SM), that is cleaved to C12-NBD-Cer1,3P, which is easily separated from other potential metabolites by thin-layer chromatography and visualized under UV light. Besides confirming that C12-NBD-Cer1,3P is the only product detected upon incubation of C12-NBD-SM with brown recluse spider venom, the method was also able to detect for the first time very low levels of activity in venom from another spider, <i>Kukulcania hibernalis</i> The simplicity of the methods makes it relatively easy to determine this signature activity of SMase D/PLD. SIGNIFICANCE STATEMENT: The sphingomyelinase D/phospholipase D that are present in the venom of the brown recluse spider and other sources cause considerable human injury, but detection of the novel sphingolipid product, ceramide 1,3-cyclic phosphate, is not easy by previously published methods. This minireview describes simple methods for detection of this activity that will be useful for studies of its occurrence in spider venoms and other biological samples, perhaps including lesions from suspected spider bites and infections.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":" ","pages":"144-154"},"PeriodicalIF":3.2,"publicationDate":"2024-02-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10877732/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41176712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery and characterization of VU0542270, the first selective inhibitor of vascular Kir6.1/SUR2B KATPchannels","authors":"Kangjun Li, Samantha J McClenahan, Changho Han, Joseph D Bungard, Upendra Rathnayake, Olivier Boutaud, Joshua A. Bauer, Emily Days, Craig W. Lindsley, Elaine L. Shelton, Jerod S. Denton","doi":"10.1124/molpharm.123.000783","DOIUrl":"https://doi.org/10.1124/molpharm.123.000783","url":null,"abstract":"Vascular smooth muscle K_ATP channels critically regulate blood flow and blood pressure by modulating vascular tone, and therefore represent attractive drug targets for treating several cardiovascular disorders. However, the lack of potent inhibitors that can selectively inhibit Kir6.1/SUR2B (vascular K_ATP) over Kir6.2/SUR1 (pancreatic K_ATP) has alluded discovery despite decades of intensive research. We therefore screened 47,872 chemically diverse compounds for novel inhibitors of heterologously expressed Kir6.1/SUR2B channels. The most potent inhibitor identified in the screen was an <em>N</em>-aryl-<em>N</em>'-benzyl urea compound termed VU0542270. VU0542270 inhibits Kir6.1/SUR2B with an IC₅₀ of approximately 100 nM but has no apparent activity toward Kir6.2/SUR1 or several other members of the Kir channel family at doses up to 30 µM (&gt;300-fold selectivity). By expressing different combinations of Kir6.1 or Kir6.2 with SUR1, SUR2A, or SUR2B, the VU0542270 binding site was localized to SUR2. Initial structure-activity relationship exploration around VU0542270 revealed basic texture related to structural elements that are required for Kir6.1/SUR2B inhibition. Analysis of the pharmacokinetic properties of VU0542270 showed that it has a short in vivo half-life due to extensive metabolism. In pressure myography experiments on isolated mouse ductus arteriosus (DA) vessels, VU0542270 induced DA constriction in a dose-dependent manner similar to that of the non-specific K_ATP channel inhibitor, glibenclamide. The discovery of VU0542270 provides conceptual proof that SUR2-specific K_ATP channel inhibitors can be developed using a molecular target-based approach and offers hope for developing cardiovascular therapeutics targeting Kir6.1/SUR2B.","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"14 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2024-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139664886","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacological Characterization of the Zebrafish (Danio Rerio) Histamine H₁ Receptor Reveals the Involvement of the Second Extracellular Loop in the Binding of Histamine.","authors":"Daniel A McNaught-Flores, Albert J Kooistra, Yu-Chia Chen, Jose-Antonio Arias-Montano, Pertti Panula, Rob Leurs","doi":"10.1124/molpharm.123.000741","DOIUrl":"10.1124/molpharm.123.000741","url":null,"abstract":"<p><p>The zebrafish (Danio rerio) histamine H₁ receptor gene (zfH₁R) was cloned in 2007 and reported to be involved in fish locomotion. Yet, no detailed characterization of its pharmacology and signaling properties have so far been reported. In this study, we pharmacologically characterized the zfH₁R expressed in HEK-293T cells by means of [³H]-mepyramine binding and G protein-signaling assays. The zfH₁R [dissociation constant (K_D), 0.7 nM] displayed similar affinity for the antagonist [³H]-mepyramine as the human histamine H₁ receptor (hH₁R) (K_D, 1.5 nM), whereas the affinity for histamine is 100-fold higher than for the human H₁R. The zfH₁R couples to Gα_q/11 proteins and activates several reporter genes, i.e., NFAT, NFϰB, CRE, VEGF, COX-2, SRE, and AP-1, and zfH₁R-mediated signaling is prevented by the Gα_q/11 inhibitor YM-254890 and the antagonist mepyramine. Molecular modeling of the zfH₁R and human H₁R shows that the binding pockets are identical, implying that variations along the ligand binding pathway could underly the differences in histamine affinity instead. Targeting differentially charged residues in extracellular loop 2 (ECL2) using site-directed mutagenesis revealed that Arg210^45x55 is most likely involved in the binding process of histamine in zfH₁R. This study aids the understanding of the pharmacological differences between H₁R orthologs and the role of ECL2 in histamine binding and provides fundamental information for the understanding of the histaminergic system in the zebrafish. SIGNIFICANCE STATEMENT: The use of the zebrafish as in vivo models in neuroscience is growing exponentially, which asks for detailed characterization of the aminergic neurotransmitter systems in this model. This study is the first to pharmacologically characterize the zebrafish histamine H₁ receptor after expression in HEK-293T cells. The results show a high pharmacological and functional resemblance with the human ortholog but also reveal interesting structural differences and unveils an important role of the second extracellular loop in histamine binding.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":" ","pages":"84-96"},"PeriodicalIF":3.2,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136398237","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"<i>β</i>-Caryophyllene Inhibits Monoacylglycerol Lipase Activity and Increases 2-Arachidonoyl Glycerol Levels In Vivo: A New Mechanism of Endocannabinoid-Mediated Analgesia?","authors":"Jost Klawitter, Wiebke Weissenborn, Iuliia Gvon, Mackenzie Walz, Jelena Klawitter, Matthew Jackson, Cristina Sempio, Sonja L Joksimovic, Touraj Shokati, Ingo Just, Uwe Christians, Slobodan M Todorovic","doi":"10.1124/molpharm.123.000668","DOIUrl":"10.1124/molpharm.123.000668","url":null,"abstract":"<p><p>The mechanisms of <i>β</i>-caryophyllene (BCP)-induced analgesia are not well studied. Here, we tested the efficacy of BCP in an acute postsurgical pain model and evaluated its effect on the endocannabinoid system. Rats were treated with vehicle and 10, 25, 50, and 75 mg/kg BCP. Paw withdrawal responses to mechanical stimuli were evaluated using an electronic von Frey anesthesiometer. Endocannabinoids, including 2-arachidonoylglycerol (2-AG), were also evaluated in plasma and tissues using high-performance liquid chromatography-tandem mass spectrometry. Monoacylglycerol lipase (MAGL) activity was evaluated in vitro as well as ex vivo. We observed a dose-dependent and time-dependent alleviation of hyperalgesia in incised paws up to 85% of the baseline value at 30 minutes after administration of BCP. We also observed dose-dependent increases in the 2-AG levels of about threefold after administration of BCP as compared with vehicle controls. Incubations of spinal cord tissue homogenates from BCP-treated rats with isotope-labeled 2-arachidonoylglycerol-d8 revealed a reduced formation of the isotope-labeled MAGL product 2-AG-d8 as compared with vehicle controls, indicating MAGL enzyme inhibition. In vitro MAGL enzyme activity assessment using 2-AG as the substrate revealed an IC₅₀ of 15.8 µM for MAGL inhibition using BCP. These data showed that BCP inhibits MAGL activity in vitro and in vivo, causing 2-AG levels to rise. Since the endocannabinoid 2-AG is a CB1 and CB2 receptor agonist, we propose that 2-AG-mediated cannabinoid receptor activation contributes to BCP's mechanism of analgesia. SIGNIFICANCE STATEMENT: <i>β</i>-Caryophyllene (BCP) consumption is relatively safe and is approved by the Food and Drug Administration as a flavoring agent, which can be used in cosmetic and food additives. BCP is a potent anti-inflammatory agent that showed substantial antihyperalgesic properties in this study of acute pain suggesting that BCP might be an alternative to opioids. This study shows an additive mechanism (monoacylglycerol lipase inhibition) by which BCP might indirectly alter CB1 and CB2 receptor activity and exhibit its pharmacological properties.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":" ","pages":"75-83"},"PeriodicalIF":3.2,"publicationDate":"2024-01-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10794982/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139403663","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inhibition of cardiac Kv4.3/KChIP2 channels by a sulfonylurea drug gliquidone","authors":"Chenxia Yang, Qinqin Li, Fang Hu, Yani Liu, KeWei Wang","doi":"10.1124/molpharm.123.000787","DOIUrl":"https://doi.org/10.1124/molpharm.123.000787","url":null,"abstract":"","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"140 9","pages":""},"PeriodicalIF":3.6,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138953297","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nanobody-mediated dualsteric engagement of the angiotensin receptor broadens biased ligand pharmacology","authors":"Nayara Braga Emidio, Brandi M. Small, Amanda R. Keller, Ross W. Cheloha, L. Wingler","doi":"10.1124/molpharm.123.000797","DOIUrl":"https://doi.org/10.1124/molpharm.123.000797","url":null,"abstract":"","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"71 1","pages":""},"PeriodicalIF":3.6,"publicationDate":"2023-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"138953033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}