Molecular Pharmacology最新文献

{"title":"Ca²⁺/calmodulin-dependent inhibitors of adenylyl cyclase 1 as novel nonopioid analgesics for chronic inflammatory pain.","authors":"Tiffany S Dwyer, Annadka Shrinidhi, Sadikshya Aryal, Martin W Berchtold, Mads Munk, Amanda H Klein, Wendy A Koss, Daniel P Flaherty, Val J Watts","doi":"10.1016/j.molpha.2026.100121","DOIUrl":"https://doi.org/10.1016/j.molpha.2026.100121","url":null,"abstract":"<p><p>Adenylyl cyclase 1 (AC1) plays an integral role in the excitatory signaling in the anterior cingulate cortex underlying chronic pain pathophysiology. Upon chronic nociceptive input, sustained Ca²⁺/calmodulin (CaM)-stimulated AC1 activity leads to the development of chronic pain. In this study, we characterize our recently reported series of pyrazolopyrimidinone amine analogs that selectively inhibit Ca²⁺/CaM-stimulated AC1 activity. Lead compounds AC10136A, AC10142A, and AC10172A exhibited potent AC1 inhibition (IC₅₀ = 140-290 nM) and complete selectivity over AC2, AC5, and AC8. All compounds showed high therapeutic indices (>300) and minimal cytotoxicity up to 100 μM. Lead compounds displayed no functional agonism at κ-opioid receptor. Further, compounds prevented and reversed μ-opioid receptor-mediated heterologous sensitization of AC1, highlighting potential utility in mitigating opioid-induced dependence. Further, chronic treatment with lead compounds failed to induce opioid-like adaptations, such as heterologous sensitization, and did not modulate expression of AC1. Mechanistic studies revealed that inhibition is Ca²⁺/CaM dependent but independent of Gα_s, suggesting preferential targeting of the active AC1 conformation. In mice, AC10142A demonstrated analgesic efficacy in the complete Freund adjuvant model of chronic inflammatory pain. Acute and repeated dosing at 48-120 h after complete Freund adjuvant treatment increased mechanical paw withdrawal thresholds and sustained analgesia over this repeated dosing. By targeting Ca²⁺/CaM-bound AC1, these inhibitors preferentially inhibit increased AC1 activity to its normal activity, demonstrating a state-dependent mechanism ideal for chronic pain treatment. Together, these findings establish AC10136A, AC10142A, and AC10172A as potent, selective, and well-tolerated AC1 inhibitors, with promising therapeutic potential for chronic pain and potentially opioid use disorder. SIGNIFICANCE STATEMENT: Adenylyl cyclase 1 (AC1) plays a key role in chronic pain sensitization and opioid use disorder, making it a promising therapeutic target. Selective pyrazolopyrimidinone amine inhibitors of AC1 potently block Ca²⁺/calmodulin-dependent activation (with IC₅₀ values of 140-290 nM), exhibit excellent in vitro safety profiles, prevent μ-opioid receptor-mediated AC1 sensitization in vitro, and demonstrate robust antiallodynic effects in vivo, positioning this compound series as a compelling nonopioid strategy for managing chronic pain and potentially addressing opioid use disorder.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 5-6","pages":"100121"},"PeriodicalIF":3.0,"publicationDate":"2026-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147840183","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":"Loss of α-cell GRK2 modulates glucagon response and supports cardiac function.","authors":"Jonathan Snyder, Lilly Underwood, Chun-Sun Jiang, Victoria Kaml, Snekha Rajasekaran, Lily Xie, C Reid Dotson, Priscila Y Sato","doi":"10.1016/j.molpha.2026.100115","DOIUrl":"10.1016/j.molpha.2026.100115","url":null,"abstract":"<p><p>Pancreatic α-cells secrete glucagon to maintain glucose homeostasis, yet the molecular mechanisms regulating hormone release are understudied. G-protein coupled receptor kinases (GRKs) regulate receptor desensitization; however, their role in α-cells remains unknown. Here, we generated an inducible α-cell-specific GRK2 knockout (αGRK2KO) mouse model to investigate the role of GRK2 in islet physiology, systemic metabolism, and cardiac function. Loss of GRK2 in α-cells reduced islet GRK2 protein by ∼20%, consistent with α-cell islet abundance, and produced negligible alterations in glucose tolerance without affecting insulin secretion. Notably, αGRK2KO mice had altered fast/fed glucagon responses, reduced adiposity, and lower body weight. Despite minimal effects on systemic glucose handling, αGRK2KO animals exhibited improved cardiac function, characterized by enhanced ejection fraction and fractional shortening, without signs of hypertrophy. High-fat, high-sucrose diet feeding abated these changes, underscoring the diet-dependent impact of α-cell GRK2. Together, these findings identify GRK2 as a previously unrecognized regulator of α-cell glucagon secretion that influences systemic energy balance and cardiac performance through endocrine crosstalk. This work establishes a framework for α-cell G protein-coupled receptor regulation and highlights GRK2 as a potential therapeutic node linking islet function, metabolism, and the heart. SIGNIFICANCE STATEMENT: This study explores the role of GRK2 in α-cell biology as a regulator of glucagon dynamics and cardiac function, thereby establishing a new endocrine link between islet signaling and cardiac biology.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 4","pages":"100115"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147530586","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":"Expression of concern: \"The Cyclopentenone Prostaglandin 15-Deoxy-delta^12,14-Prostaglandin J₂ Attenuates the Development of Acute and Chronic Inflammation\" [Mol. Pharmacol. 2002; 61: 997-1007] by Cuzzocrea S, Wayman N, Mazzon E, et al.","authors":"","doi":"10.1016/j.molpha.2026.100107","DOIUrl":"https://doi.org/10.1016/j.molpha.2026.100107","url":null,"abstract":"","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 4","pages":"100107"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817614","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":"Extracellular domain-dependent modulation of class B1 G-protein-coupled receptor signaling.","authors":"Alex D White, Leah R Padgett, Francis S Willard","doi":"10.1016/j.molpha.2026.100111","DOIUrl":"10.1016/j.molpha.2026.100111","url":null,"abstract":"<p><p>The class B1 subfamily of G-protein-coupled receptors (GPCRs) comprises 15 members that respond to endogenous peptides to regulate an array of important physiological processes. Activation by peptide ligands is considered to follow a 2-step binding mechanism that involves an initial interaction with the receptor ectodomain (ECD) followed by engagement with transmembrane regions that collectively result in effector coupling. This model suggests that the ECD acts as an affinity trap that generally does not regulate downstream signaling events. Here, we show that members of the glucagon receptor subfamily of class B1 GPCRs contain a conserved 6-amino acid motif within their ECDs and that individual residues regulate cAMP and/or βarr pathways by either allosterically promoting effector coupling or as determinants required for proper receptor expression and function via modulation of posttranslational receptor glycosylation. We also highlight that this conserved motif surprisingly alters observed signaling phenomena in both a ligand- and receptor-dependent manner. Our study unveils an unexpected role of the ECD in regulating class B1 GPCR signaling properties independently of ligand binding affinity and suggests that the well-established 2-step binding paradigm requires further investigation to understand the nuances of activation mechanisms for this receptor class. SIGNIFICANCE STATEMENT: Class B1 G-protein-coupled receptors respond to endogenous peptide ligands to fine-tune biological processes. These receptors contain the hallmark structural feature of a large ectodomain at their N-termini that has been shown to be critical for ligand binding affinity, but whether this region regulates downstream signaling remains unclear. We identify a conserved site within the glucagon-like peptide-1 receptor, glucagon receptor, and glucose-dependent insulinotropic polypeptide receptor localized to the ectodomain that modulates both effector coupling as well as proper receptor expression and functionality in ligand- and receptor-dependent manners. Given the benefit of targeting these receptors in the treatment of type 2 diabetes and obesity, our findings may provide insights toward a better understanding of their activation mechanisms and facilitate rational drug discovery approaches.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 4","pages":"100111"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147372955","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":"Expression of concern: \"Adelmidrol, a Palmitoylethanolamide Analogue, as a New PharmacologicalTreatment for the Management of Inflammatory Bowel Disease\" [Mol. Pharmacol. 2016; 90: 549-561] by Cordaro M, Impellizzeri D, Gugliandolo E, et al.","authors":"","doi":"10.1016/j.molpha.2026.100109","DOIUrl":"https://doi.org/10.1016/j.molpha.2026.100109","url":null,"abstract":"","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 4","pages":"100109"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817633","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":"Expression of concern: \"Glucocorticoid-Induced Tumor Necrosis Factor Receptor-Related (GITR)-Fc Fusion Protein Inhibits GITR Triggering and Protects from the Inflammatory Response after Spinal Cord Injury\" [Mol. Pharmacol. 2008; 73: 1610-1621] by Nocentini G, Cuzzocrea S, Genovese T, et al.","authors":"","doi":"10.1016/j.molpha.2026.100108","DOIUrl":"https://doi.org/10.1016/j.molpha.2026.100108","url":null,"abstract":"","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 4","pages":"100108"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147817629","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":"Differential impacts of exon 1-associated and exon 11-associated variants of the rat mu opioid receptor gene, Oprm1, on buprenorphine- and morphine-induced analgesia and respiratory depression in male rats.","authors":"Tiffany Zhang, Jin Xu, Valerie P Le Rouzic, Yudelca Ogando, Ayma F Malik, Raymond Chien, Miyasaka Yoshiki, Tomoji Mashimo, Thomas L Saunders, Channabasavaiah B Gurumurthy, Ying-Xian Pan","doi":"10.1016/j.molpha.2026.100112","DOIUrl":"10.1016/j.molpha.2026.100112","url":null,"abstract":"<p><p>Buprenorphine has long been recognized as a mu opioid agonist with a distinctive and intricate pharmacological profile. It is a partial agonist at the mu opioid receptor, an antagonist at the kappa and delta opioid receptors, and an agonist at the nociception opioid receptor. Similar to other mu agonists such as morphine and fentanyl, buprenorphine can produce side effects, including tolerance, physical dependence, respiratory depression, and addiction. The mu opioid receptor gene, OPRM1, undergoes extensive alternative splicing, generating an array of splice variants or isoforms, which are conserved from rodents to humans. These splice variants can be categorized into 2 main types, exon 1 (E1)-associated variants and exon 11 (E11)-associated variants. E1-associated variants primarily consist of full-length, 7-transmembrane C-terminal variants, whereas E11-associated variants are typically truncated 6-transmembrane variants. Previous studies established that buprenorphine analgesia in mice is dependent on both E1- and E11-associated variants. However, the role of these variants in buprenorphine analgesia and respiratory depression in rats remains unclear. In this study, we used CRISPR/Cas9 technology to develop 2 rat Oprm1 gene-targeting models in which E1- and E11-associated variants were selectively disrupted, aiming to investigate their roles in buprenorphine and morphine's actions. The results showed that both E1- and E11-associated variants are essential for buprenorphine's analgesic and respiratory depressional effects in rats, whereas morphine's effects are solely attributed to the E1-associated variants. These findings provide new and important insights into the distinct contributions of the E1- and E11-associated variants to the pharmacological actions of buprenorphine and morphine. SIGNIFICANCE STATEMENT: Differential dependences of buprenorphine and morphine analgesia and respiratory depression on Oprm1 exon 1- and exon 11-associated variants revealed in rat gene-targeting models provide new and important insights into unique contributions of these variants to buprenorphine and morphine actions.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 4","pages":"100112"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147372875","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":"Corrigendum to \"A subunit-selective negative allosteric modulator of GluN1/GluN3A glycine-activated receptor\" [Molecular Pharmacology 108 (2026) 100104].","authors":"Leon Jacobs, TrangKimberly T Nguyen, Adam McCallum, Matt P Epplin, Riley E Perszyk, Scott J Myers, Ken Liu, Yanli Yang, Aletta E Van der Westhuyzen, Kelsey A Nocilla, James Allen, Elijah Z Ullman, Ding Liu, Yufei Du, Hongjie Yuan, Dennis C Liotta, Stephen F Traynelis","doi":"10.1016/j.molpha.2026.100118","DOIUrl":"10.1016/j.molpha.2026.100118","url":null,"abstract":"","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 4","pages":"100118"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147593224","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":"Expressions of Concern, Corrigenda, and a Retraction.","authors":"Beverley Greenwood-Van Meerveld, John J G Tesmer, Michael Jarvis","doi":"10.1016/j.molpha.2026.100106","DOIUrl":"10.1016/j.molpha.2026.100106","url":null,"abstract":"","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":" ","pages":"100106"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147618718","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":"Elucidating the binding and metabolic interactions of sunitinib and sorafenib with Cytochrome P450s CYP2U1 and CYP2D6.","authors":"Tiffany Y-C Tang, Yupeng Li, Peter Chapman, Emad Tajkhorshid, Aditi Das","doi":"10.1016/j.molpha.2026.100114","DOIUrl":"10.1016/j.molpha.2026.100114","url":null,"abstract":"<p><p>Cytochrome P450 2U1 (CYP2U1) is an extrahepatic monooxygenase that metabolizes both endogenous fatty acids and xenobiotic substrates. Because of its high expression in both healthy and cancerous thymus tissues, this study investigated CYP2U1-mediated biotransformation of 2 tumor-targeting tyrosine kinase inhibitors, sorafenib and sunitinib, both are commonly prescribed for thymus cancers. Recombinantly expressed CYP2U1 and CYP2D6 were incorporated into nanodiscs, and their metabolism of sorafenib and sunitinib was investigated. Liquid chromatography-tandem mass spectrometry metabolite profiling revealed that both CYP2U1 and CYP2D6 nanodiscs oxidized sorafenib to generate sorafenib N-oxide and both enzymes catalyzed the dealkylation of sunitinib to form N-desethyl sunitinib. Spectroscopic studies (UV-Visible and fluorescence) confirmed favorable binding interactions of CYP2U1 and CYP2D6 to both drugs tested. Molecular dynamics simulations demonstrated binding of sorafenib and sunitinib in the CYP2U1 active site and identified key interactions between the drug and key residues at the enzyme's active site. Rates of metabolite formation were quantified by targeted metabolomics, and inhibition of tyrosine kinase was assessed by ELISA assay. Both the parent compound sorafenib and metabolite sorafenib N-oxide showed similar inhibitory effects on cellular migration in HepG2 cells. The metabolite sorafenib N-oxide was approximately twice as potent as the parent compound in inhibiting cancer cell migration. In contrast, N-desethyl sunitinib failed to show similar extent of inhibition. Together, these findings highlight the potential role of extrahepatic CYP2U1 in the local metabolism of tyrosine kinase inhibitors and suggest that CYP2U1-mediated transformations directly influence antitumor efficacy at thymic tumor sites. SIGNIFICANCE STATEMENT: Understanding the interactions between cytochrome P450 2U1 and cytochrome P450 2D6 in nanodiscs and thymus tumor-targeting drugs, sorafenib and sunitinib, led to discovery of new bioactive metabolites that carry differential anticancer properties compared with their parent compounds.</p>","PeriodicalId":18767,"journal":{"name":"Molecular Pharmacology","volume":"108 4","pages":"100114"},"PeriodicalIF":3.0,"publicationDate":"2026-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147633937","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}