A  B  C  D  E  F  G  H  I  J  K  L  M  N  O  P  Q  R  S  T  U  V  W  X  Y  Z  

        1 2 3 | Last   [Sort alphabetically]   [Restore default list]

  Subjects -> PHARMACY AND PHARMACOLOGY (Total: 575 journals)
Showing 1 - 200 of 253 Journals sorted by number of followers
Nature Reviews Drug Discovery     Full-text available via subscription   (Followers: 332)
International Journal of Drug Policy     Hybrid Journal   (Followers: 254)
Journal of Clinical Oncology     Hybrid Journal   (Followers: 242)
Journal of Medicinal Chemistry     Hybrid Journal   (Followers: 157)
Journal of Pharmaceutical Sciences     Hybrid Journal   (Followers: 155)
Drugs     Full-text available via subscription   (Followers: 146)
Advanced Drug Delivery Reviews     Hybrid Journal   (Followers: 98)
Pharmaceutical Research     Hybrid Journal   (Followers: 94)
European Journal of Pharmaceutical Sciences     Hybrid Journal   (Followers: 86)
Drug Safety     Full-text available via subscription   (Followers: 83)
Annals of Pharmacotherapy     Hybrid Journal   (Followers: 56)
Biomaterials     Hybrid Journal   (Followers: 54)
Clinical Pharmacology & Therapeutics     Hybrid Journal   (Followers: 44)
Regulatory Toxicology and Pharmacology     Hybrid Journal   (Followers: 42)
Journal of Controlled Release     Hybrid Journal   (Followers: 38)
Annual Review of Pharmacology and Toxicology     Full-text available via subscription   (Followers: 38)
International Journal of Pharmaceutics     Hybrid Journal   (Followers: 37)
Clinical Therapeutics     Hybrid Journal   (Followers: 34)
European Journal of Pharmaceutics and Biopharmaceutics     Hybrid Journal   (Followers: 34)
Pharmacoepidemiology and Drug Safety     Hybrid Journal   (Followers: 33)
British Journal of Clinical Pharmacology     Hybrid Journal   (Followers: 32)
Journal of Pharmacy and Pharmacology     Full-text available via subscription   (Followers: 31)
Drug Development and Industrial Pharmacy     Hybrid Journal   (Followers: 29)
PharmacoEconomics     Full-text available via subscription   (Followers: 27)
Clinical Pharmacokinetics     Full-text available via subscription   (Followers: 27)
AAPS Journal     Hybrid Journal   (Followers: 26)
Critical Reviews in Toxicology     Hybrid Journal   (Followers: 25)
Journal of Clinical Psychopharmacology     Hybrid Journal   (Followers: 24)
International Journal of Pharmacy Practice     Full-text available via subscription   (Followers: 24)
Toxicology and Applied Pharmacology     Hybrid Journal   (Followers: 24)
Chemical Research in Toxicology     Hybrid Journal   (Followers: 22)
Journal of Pharmacokinetics and Pharmacodynamics     Hybrid Journal   (Followers: 22)
Journal of Pain & Palliative Care Pharmacotherapy     Hybrid Journal   (Followers: 21)
Trends in Pharmacological Sciences     Full-text available via subscription   (Followers: 20)
Journal of Applied Toxicology     Hybrid Journal   (Followers: 19)
Journal of Clinical Pharmacology     Hybrid Journal   (Followers: 19)
Pharmaceutical Development and Technology     Hybrid Journal   (Followers: 19)
American Journal of Cardiovascular Drugs     Hybrid Journal   (Followers: 19)
Clinical Trials     Hybrid Journal   (Followers: 18)
Toxicology     Hybrid Journal   (Followers: 18)
Journal of Pharmaceutical and Biomedical Analysis     Hybrid Journal   (Followers: 18)
Clinical Toxicology     Hybrid Journal   (Followers: 18)
International Journal of Toxicology     Hybrid Journal   (Followers: 17)
Critical Reviews in Clinical Laboratory Sciences     Hybrid Journal   (Followers: 16)
Journal of Clinical Pharmacy and Therapeutics     Hybrid Journal   (Followers: 16)
Journal of Natural Products     Hybrid Journal   (Followers: 16)
Pharmaceutical Statistics     Hybrid Journal   (Followers: 15)
Toxicology Letters     Hybrid Journal   (Followers: 15)
Journal of Pharmacy Practice     Hybrid Journal   (Followers: 15)
Psychopharmacology     Hybrid Journal   (Followers: 15)
Basic & Clinical Pharmacology & Toxicology     Hybrid Journal   (Followers: 14)
Cardiovascular Drugs and Therapy     Hybrid Journal   (Followers: 14)
European Journal of Clinical Pharmacology     Hybrid Journal   (Followers: 14)
Current Medicinal Chemistry     Hybrid Journal   (Followers: 13)
American Journal of Therapeutics     Hybrid Journal   (Followers: 13)
Drug and Chemical Toxicology     Hybrid Journal   (Followers: 13)
Journal of the American Pharmacists Association     Full-text available via subscription   (Followers: 13)
Clinical Research and Regulatory Affairs     Hybrid Journal   (Followers: 12)
Seminars in Hematology     Hybrid Journal   (Followers: 12)
Drug Discovery Today: Technologies     Full-text available via subscription   (Followers: 12)
Current Pharmaceutical Design     Hybrid Journal   (Followers: 12)
Journal of Oncology Pharmacy Practice     Hybrid Journal   (Followers: 12)
Journal of Psychopharmacology     Hybrid Journal   (Followers: 11)
Biopharmaceutics and Drug Disposition     Hybrid Journal   (Followers: 11)
Toxicology in Vitro     Hybrid Journal   (Followers: 11)
Drug Development Research     Hybrid Journal   (Followers: 11)
Drug Metabolism and Disposition     Hybrid Journal   (Followers: 11)
Seminars in Oncology Nursing     Full-text available via subscription   (Followers: 10)
Biochemical Pharmacology     Hybrid Journal   (Followers: 10)
Journal of Separation Science     Hybrid Journal   (Followers: 10)
CNS Drugs     Full-text available via subscription   (Followers: 10)
Current Pharmaceutical Biotechnology     Hybrid Journal   (Followers: 10)
Journal of Medical Marketing     Hybrid Journal   (Followers: 10)
Drugs & Aging     Full-text available via subscription   (Followers: 10)
European Neuropsychopharmacology     Hybrid Journal   (Followers: 9)
Food Additives & Contaminants Part A     Hybrid Journal   (Followers: 9)
Journal of Pharmacology and Experimental Therapeutics     Hybrid Journal   (Followers: 9)
Environmental Toxicology and Pharmacology     Hybrid Journal   (Followers: 9)
Medicinal Chemistry     Hybrid Journal   (Followers: 9)
Biometrical Journal     Hybrid Journal   (Followers: 9)
Drugs & Therapy Perspectives     Full-text available via subscription   (Followers: 9)
Prescriber     Hybrid Journal   (Followers: 9)
ChemMedChem     Hybrid Journal   (Followers: 9)
Current Opinion in Pharmacology     Hybrid Journal   (Followers: 9)
European Journal of Pharmacology     Hybrid Journal   (Followers: 8)
Inhalation Toxicology     Hybrid Journal   (Followers: 8)
Antiviral Research     Hybrid Journal   (Followers: 8)
Drug Metabolism Reviews     Hybrid Journal   (Followers: 8)
Progress in Neuro-Psychopharmacology and Biological Psychiatry     Hybrid Journal   (Followers: 8)
Human & Experimental Toxicology     Hybrid Journal   (Followers: 8)
Drug Delivery     Open Access   (Followers: 8)
BioDrugs     Full-text available via subscription   (Followers: 8)
Frontiers in Drug Design & Discovery     Hybrid Journal   (Followers: 8)
Expert Review of Pharmacoeconomics & Outcomes Research     Full-text available via subscription   (Followers: 8)
Experimental and Clinical Psychopharmacology     Full-text available via subscription   (Followers: 7)
Toxicology Mechanisms and Methods     Hybrid Journal   (Followers: 7)
Journal of Pharmacological and Toxicological Methods     Hybrid Journal   (Followers: 7)
Clinical and Experimental Pharmacology and Physiology     Hybrid Journal   (Followers: 7)
Scandinavian Journal of Clinical and Laboratory Investigation     Hybrid Journal   (Followers: 7)
Epilepsy Research     Hybrid Journal   (Followers: 7)
Clinical Drug Investigation     Full-text available via subscription   (Followers: 7)
Journal of Veterinary Pharmacology and Therapeutics     Hybrid Journal   (Followers: 6)
Toxicology and Industrial Health     Hybrid Journal   (Followers: 6)
Skin Pharmacology and Physiology     Full-text available via subscription   (Followers: 6)
Journal of Cardiovascular Pharmacology     Hybrid Journal   (Followers: 6)
AAPS PharmSciTech     Hybrid Journal   (Followers: 6)
Current Drug Discovery Technologies     Hybrid Journal   (Followers: 6)
Current Drug Delivery     Hybrid Journal   (Followers: 6)
Current Therapeutic Research     Open Access   (Followers: 6)
Expert Review of Cardiovascular Therapy     Full-text available via subscription   (Followers: 6)
Neuropharmacology     Hybrid Journal   (Followers: 5)
Current Drug Metabolism     Hybrid Journal   (Followers: 5)
Fitoterapia     Hybrid Journal   (Followers: 5)
Expert Review of Molecular Diagnostics     Full-text available via subscription   (Followers: 5)
Expert Review of Anti-infective Therapy     Full-text available via subscription   (Followers: 5)
Anti-Infective Agents     Hybrid Journal   (Followers: 5)
Toxicon     Hybrid Journal   (Followers: 5)
Medicinal Research Reviews     Hybrid Journal   (Followers: 5)
Investigational New Drugs     Hybrid Journal   (Followers: 5)
Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry     Hybrid Journal   (Followers: 5)
Current Cancer Therapy Reviews     Hybrid Journal   (Followers: 5)
Reviews of Physiology, Biochemistry and Pharmacology     Hybrid Journal   (Followers: 4)
Planta Medica     Hybrid Journal   (Followers: 4)
Current Vascular Pharmacology     Hybrid Journal   (Followers: 4)
Pharmaceutical Medicine     Full-text available via subscription   (Followers: 4)
Journal of Child and Adolescent Psychopharmacology     Hybrid Journal   (Followers: 4)
CNS Drug Reviews     Open Access   (Followers: 4)
Inpharma Weekly     Full-text available via subscription   (Followers: 4)
Journal of Labelled Compounds and Radiopharmaceuticals     Hybrid Journal   (Followers: 4)
Immunopharmacology and Immunotoxicology     Hybrid Journal   (Followers: 4)
International Journal of Pharmaceutical and Healthcare Marketing     Hybrid Journal   (Followers: 4)
Inflammation Research     Hybrid Journal   (Followers: 4)
Cancer Chemotherapy and Pharmacology     Hybrid Journal   (Followers: 4)
International Journal of Neuropsychopharmacology     Open Access   (Followers: 3)
Pharmacology & Therapeutics     Hybrid Journal   (Followers: 3)
Physiology International     Full-text available via subscription   (Followers: 3)
Cardiovascular Therapeutics     Open Access   (Followers: 3)
ASSAY and Drug Development Technologies     Hybrid Journal   (Followers: 3)
Pharmacopsychiatry     Hybrid Journal   (Followers: 3)
Chemotherapy     Full-text available via subscription   (Followers: 3)
Therapeutic Drug Monitoring     Hybrid Journal   (Followers: 3)
Current Drug Therapy     Hybrid Journal   (Followers: 3)
Research in Social and Administrative Pharmacy     Hybrid Journal   (Followers: 3)
PharmacoEconomics & Outcomes News     Full-text available via subscription   (Followers: 3)
Journal of Aerosol Medicine and Pulmonary Drug Delivery     Hybrid Journal   (Followers: 3)
Journal of Ethnopharmacology     Hybrid Journal   (Followers: 3)
Drug Resistance Updates     Hybrid Journal   (Followers: 3)
Journal of Pain Management & Medicine     Open Access   (Followers: 3)
Journal of Infection and Chemotherapy     Hybrid Journal   (Followers: 3)
Journal of Cardiovascular Pharmacology and Therapeutics     Hybrid Journal   (Followers: 3)
Current Pharmacogenomics and Personalized Medicine     Hybrid Journal   (Followers: 3)
Acta Pharmacologica Sinica     Hybrid Journal   (Followers: 3)
Microbial Drug Resistance     Hybrid Journal   (Followers: 3)
Frontiers in Medicinal Chemistry     Hybrid Journal   (Followers: 3)
Human Psychopharmacology Clinical and Experimental     Hybrid Journal   (Followers: 3)
BMC Pharmacology     Open Access   (Followers: 2)
The Brown University Psychopharmacology Update     Hybrid Journal   (Followers: 2)
International Clinical Psychopharmacology     Hybrid Journal   (Followers: 2)
Canadian Journal of Physiology and Pharmacology     Hybrid Journal   (Followers: 2)
Journal of Drug Targeting     Hybrid Journal   (Followers: 2)
Inflammopharmacology     Hybrid Journal   (Followers: 2)
Journal of Inflammation     Open Access   (Followers: 2)
Fundamental & Clinical Pharmacology     Hybrid Journal   (Followers: 2)
Behavioural Pharmacology     Hybrid Journal   (Followers: 2)
Vascular Pharmacology     Hybrid Journal   (Followers: 2)
Pulmonary Pharmacology & Therapeutics     Hybrid Journal   (Followers: 2)
Biomedicine & Pharmacotherapy     Full-text available via subscription   (Followers: 2)
Clinical Neuropharmacology     Hybrid Journal   (Followers: 2)
Drugs in R & D     Full-text available via subscription   (Followers: 2)
International Immunopharmacology     Hybrid Journal   (Followers: 2)
Pharmacology Biochemistry and Behavior     Hybrid Journal   (Followers: 2)
Letters in Drug Design & Discovery     Hybrid Journal   (Followers: 2)
Archiv der Pharmazie     Hybrid Journal   (Followers: 2)
Pharmacological Reviews     Hybrid Journal   (Followers: 2)
Molecular Pharmacology     Hybrid Journal   (Followers: 2)
Journal of Microencapsulation: Microcapsules, Liposomes, Nanoparticles, Microcells, Microspheres     Hybrid Journal   (Followers: 2)
Toxicological & Environmental Chemistry     Hybrid Journal   (Followers: 2)
Particulate Science and Technology: An International Journal     Hybrid Journal   (Followers: 1)
Pharmacological Research     Hybrid Journal   (Followers: 1)
Current Enzyme Inhibition     Hybrid Journal   (Followers: 1)
Journal of Neuroimmune Pharmacology     Hybrid Journal   (Followers: 1)
Current Pharmaceutical Analysis     Hybrid Journal   (Followers: 1)
Current Neuropharmacology     Hybrid Journal   (Followers: 1)
Pharmacogenetics and Genomics     Hybrid Journal   (Followers: 1)
Journal of Texture Studies     Hybrid Journal   (Followers: 1)
Pharmaceutical Biology     Open Access  
Journal of Liposome Research     Hybrid Journal  
Toxin Reviews     Hybrid Journal  
Kaohsiung Journal of Medical Sciences     Open Access  
Redox Report     Open Access  
Pharmacology     Full-text available via subscription  
Pharmaceutical Chemistry Journal     Hybrid Journal  
NeuroMolecular Medicine     Hybrid Journal  
Journal of Ocular Pharmacology and Therapeutics     Hybrid Journal  
Harm Reduction Journal     Open Access  
Current Nanoscience     Hybrid Journal  
Infectious Disorders - Drug Targets     Hybrid Journal  
Current Bioactive Compounds     Hybrid Journal  
Cancer Biotherapy & Radiopharmaceuticals     Hybrid Journal  
Autonomic & Autacoid Pharmacology     Hybrid Journal  

        1 2 3 | Last   [Sort alphabetically]   [Restore default list]

Similar Journals
Journal Cover
Molecular Pharmacology
Journal Prestige (SJR): 2.076
Citation Impact (citeScore): 4
Number of Followers: 2  
 
  Hybrid Journal Hybrid journal (It can contain Open Access articles)
ISSN (Online) 1521-0111
Published by ASPET Homepage  [4 journals]
  • Structural Basis for the Allosteric Inhibition of Hypoxia-Inducible Factor
           2 by Belzutifan [Articles]

    • Free pre-print version: Loading...

      Authors: Ren, X; Diao, X, Zhuang, J, Wu, D.
      Pages: 240 - 247
      Abstract: Hypoxia-inducible factor (HIF)-2α and its obligate heterodimerization partner aryl hydrocarbon receptor nuclear translocator (ARNT), are both members of the basic helix-loop-helix-PER-ARNT-SIM transcription factor family. Previous studies have identified HIF-2α as a key oncogenic driver in clear cell renal cell carcinoma (ccRCC), rendering it a promising drug target for this type of kidney cancer. Belzutifan is the first HIF-2α inhibitor approved for treating ccRCC and other cancers associated with the von Hippel-Lindau disease. However, the detailed inhibitory mechanism of belzutifan at molecular level is still unclear. Here we obtained the crystal structure of HIF-2α–ARNT heterodimer in complex with belzutifan at 2.75 Å resolution. The complex structure shows that belzutifan binds into the PAS-B pocket of HIF-2α, and it destabilizes the dimerization of HIF-2α and ARNT through allosteric effects mainly mediated by the key residue M252 of HIF-2α near the dimer interface. We further explored the inhibitory effects of belzutifan using biochemical and functional assays. The time-resolved fluorescence energy transfer–based binding assay showed that belzutifan disrupts the dimerization of HIF-2α and ARNT with a Ki value of 23 nM. The luciferase reporter assay indicated that belzutifan can efficiently inhibit the transcriptional activity of HIF-2α with an IC50 value of 17 nM. Besides, the real-time polymerase chain reaction assay illustrated that belzutifan can reduce the expression of HIF-2α downstream genes in 786-O kidney cancer cells in a dose-dependent manner. Our work reveals the molecular mechanism by which belzutifan allosterically inhibits HIF-2α and provides valuable information for the subsequent drug development targeting HIF-2α.SIGNIFICANCE STATEMENTThe basic helix-loop-helix-PER-ARNT-SIM (bHLH-PAS) family of transcription factors are an emerging group of small-molecule drug targets. Belzutifan, originally developed by Peloton Therapeutics, is the first Food and Drug Administration–approved drug directly binding to a bHLH-PAS protein, the hypoxia-inducible factor (HIF)-2α. Based on the protein-drug complex structure, biochemical binding assays, and functional profiling of downstream gene expression, this study reveals the regulatory mechanism of how belzutifan allosterically destabilizes HIF-2α’s heterodimerization with its obligate partner protein, thus reducing their transcriptional activity that links to tumor progression.
      PubDate: 2022-11-04T11:24:20-07:00
      DOI: 10.1124/molpharm.122.000525
      Issue No: Vol. 102, No. 6 (2022)
       
  • Cancer-Type Organic Anion Transporting Polypeptide 1B3 Is Localized in
           Lysosomes and Mediates Resistance against Kinase Inhibitors [Articles]

    • Free pre-print version: Loading...

      Authors: Haberkorn, B; Oswald, S, Kehl, N, Gessner, A, Taudte, R. V, Dobert, J. P, Zunke, F, Fromm, M. F, König, J.
      Pages: 248 - 258
      Abstract: Cancer-type organic anion transporting polypeptide 1B3 (Ct-OATP1B3), a splice variant of the hepatic uptake transporter OATP1B3 (liver-type), is expressed in several tumor entities, including colorectal carcinoma (CRC) and breast cancer. In CRC, high OATP1B3 expression has been associated with reduced progression-free and overall survival. Several kinase inhibitors used for antitumor treatment are substrates and/or inhibitors of OATP1B3 (e.g., encorafenib, vemurafenib). The functional importance of Ct-OATP1B3 has not been elucidated so far. Human embryonic kidney 293 cells stably overexpressing Ct-OATP1B3 protein were established and compared with control cells. Confocal laser scanning microscopy, immunoblot, and proteomics-based expression analysis demonstrated that Ct-OATP1B3 protein is intracellularly localized in lysosomes of stably transfected cells. Cytotoxicity experiments showed that cells recombinantly expressing the Ct-OATP1B3 protein were more resistant against the kinase inhibitor encorafenib compared with control cells [e.g., encorafenib (100 µM) survival rates: 89.5% versus 52.8%]. In line with these findings, colorectal cancer DLD1 cells endogenously expressing Ct-OATP1B3 protein had poorer survival rates when the OATP1B3 substrate bromosulfophthalein (BSP) was coincubated with encorafenib or vemurafenib compared with the incubation with the kinase inhibitor alone. This indicates a competitive inhibition of Ct-OATP1B3–mediated uptake into lysosomes by BSP. Accordingly, mass spectrometry-based drug analysis of lysosomes showed a reduced lysosomal accumulation of encorafenib in DLD1 cells additionally exposed to BSP. These results demonstrate that Ct-OATP1B3 protein is localized in the lysosomal membrane and can mediate transport of certain kinase inhibitors into lysosomes, revealing a new mechanism of resistance.SIGNIFICANCE STATEMENTThis study describes the characterization of a tumor-associated splice variant (cancer-type organic anion transporting polypeptide; Ct-OATP1B3) of the liver-type OATP1B3 protein (Lt-OATP1B3). This variant is localized in lysosomes mediating resistance against kinase inhibitors that are substrates of this transport protein by transporting them into lysosomes and thereby reducing the cytoplasmic concentrations of these drugs. Therefore, the expression of the cancer-type OATP1B3 protein is associated with a better survival of cells, revealing a new mechanism of drug resistance.
      PubDate: 2022-11-04T11:24:20-07:00
      DOI: 10.1124/molpharm.122.000539
      Issue No: Vol. 102, No. 6 (2022)
       
  • Differential Enantiomer-Specific Signaling of Cannabidiol at CB1 Receptors
           [Articles]

    • Free pre-print version: Loading...

      Authors: Bosquez-Berger, T; Wilson, S, Iliopoulos-Tsoutsouvas, C, Jiang, S, Wager-Miller, J, Nikas, S. P, Mackie, K. P, Makriyannis, A, Straiker, A.
      Pages: 259 - 268
      Abstract: The two main constituents of cannabis are 9-tetrahydrocannabinol (THC) and cannabidiol (CBD). While 9-THC pharmacology has been studied extensively, CBD–long considered inactive–is now the subject of vigorous research related to epilepsy, pain, and inflammation and is popularly embraced as a virtual cure-all. However, our understanding of CBD pharmacology remains limited, although CBD inhibits cannabinoid CB1 receptor signaling, likely as a negative allosteric modulator. Cannabis synthesizes (-)-CBD, but CBD can also exist as an enantiomer, (+)-CBD. We enantioselectively synthesized both CBD enantiomers using established conditions and describe here a new, practical, and reliable, NMR-based method for confirming the enantiomeric purity of two CBD enantiomers. We also investigated the pharmacology of (+)-CBD in autaptic hippocampal neurons, a well-characterized neuronal model of endogenous cannabinoid signaling, and in CHO-K1 cells. We report the inhibition constant for displacing CP55,940 at CB1 by (+)-CBD, is 5-fold lower than (-)-CBD. We find that (+)-CBD is ~10 times more potent at inhibiting depolarization-induced suppression of excitation (DSE), a form of endogenous cannabinoid-mediated retrograde synaptic plasticity. (+)-CBD also inhibits CB1 suppression of cAMP accumulation but with less potency, indicating that the signaling profiles of the enantiomers differ in a pathway-specific manner. In addition, we report that (+)-CBD stereoselectively and potently activates the sphingosine-1 phosphate (S1P) receptors, S1P1 and S1P3. These results provide an attractive method for synthesizing and distinguishing enantiomers of CBD and related phytocannabinoids and provide further evidence that these enantiomers have their own unique and interesting signaling properties.SIGNIFICANCE STATEMENTCannabidiol (CBD) is the subject of considerable scientific and popular interest, but we know little of the enantiomers of CBD. We find that the enantiomer (+)-CBD is substantially more potent inhibitor of cannabinoid CB1 receptors and that it activates sphingosine-1-phosphate receptors in an enantiomer-specific manner; we have additionally developed an improved method for the synthesis of enantiomers of CBD and related compounds.
      PubDate: 2022-11-11T13:13:33-08:00
      DOI: 10.1124/molpharm.121.000305
      Issue No: Vol. 102, No. 6 (2022)
       
  • Coincident Regulation of PLC{beta} Signaling by Gq-Coupled and {mu}-Opioid
           Receptors Opposes Opioid-Mediated Antinociception [Articles]

    • Free pre-print version: Loading...

      Authors: Sanchez, G. A; Jutkiewicz, E. M, Ingram, S, Smrcka, A. V.
      Pages: 269 - 279
      Abstract: Pain management is an important problem worldwide. The current frontline approach for pain management is the use of opioid analgesics. The primary analgesic target of opioids is the μ-opioid receptor (MOR). Deletion of phospholipase Cβ3 (PLCβ3) or selective inhibition of Gβ regulation of PLCβ3 enhances the potency of the antinociceptive effects of morphine suggesting a novel strategy for achieving opioid-sparing effects. Here we investigated a potential mechanism for regulation of PLC signaling downstream of MOR in human embryonic kidney 293 cells and found that MOR alone could not stimulate PLC but rather required a coincident signal from a Gq-coupled receptor. Knockout of PLCβ3 or pharmacological inhibition of its upstream regulators, Gβ or Gq, ex vivo in periaqueductal gray slices increased the potency of the selective MOR agonist [D-Ala2, N-Me-Phe4, Gly5-ol]-enkephalin acetate salt in inhibiting presynaptic GABA release. Finally, inhibition of Gq- G protein-coupled receptor coupling in mice enhanced the antinociceptive effects of morphine. These data support a model where Gq and Gβ-dependent signaling cooperatively regulate PLC activation to decrease MOR-dependent antinociceptive potency. Ultimately, this could lead to identification of new non-MOR targets that would allow for lower-dose utilization of opioid analgesics.SIGNIFICANCE STATEMENTPrevious work demonstrated that deletion of phospholipase Cβ3 (PLCβ3) in mice potentiates μ-opioid receptor (MOR)-dependent antinociception. How PLCβ3 is regulated downstream of MOR had not been clearly defined. We show that PLC-dependent diacylglycerol generation is cooperatively regulated by MOR-Gβ and Gq-coupled receptor signaling through PLCβ3 and that blockade of either Gq-signaling or Gβ signaling enhances the potency of opioids in ex vivo brain slices and in vivo. These results reveal potential novel strategies for improving opioid analgesic potency and safety.
      PubDate: 2022-11-11T13:13:33-08:00
      DOI: 10.1124/molpharm.122.000541
      Issue No: Vol. 102, No. 6 (2022)
       
  • Transcriptional Regulation, Signaling Pathways, and Subcellular
           Localization of Corticotropin-Releasing Factor Receptors in the Central
           Nervous System [Minireview]

    • Free pre-print version: Loading...

      Authors: Amado, P; Zegers, J, Yarur, H. E, Gysling, K.
      Pages: 280 - 287
      Abstract: Corticotropin-releasing factor (CRF) receptors CRF-R1 and CRF-R2 are differentially distributed in body tissues, and although they respond differentially to stimuli due to their association with different signaling pathways, both receptors have a fundamental role in the response and adaptation to stressful stimuli. Here, we summarize the reported data on different forms of CRF-R1 and CRF-R2 regulation as well as on their subcellular localization. Although the presence of R1 has been described at pre- and postsynaptic sites, R2 is mainly associated with postsynaptic densities. Different studies have provided valuable information on how these receptors regulate responses at a central level, elucidating different and sometimes synergistic roles in response to stress, but despite their high sequence identity, both receptors have been described to be differentially regulated both by their ligands and by transcriptional factors. To date, and from the point of view of their promoter sequences, it has not yet been reported how the different consensus sites identified in silico could be modulating the transcriptional regulation and expression of the receptors under different conditions, which strongly limits the full understanding of their differential functions, providing a wide field to increase and expand the study of the regulation and role of CRF receptors in the CRF system.SIGNIFICANCE STATEMENTA large number of physiological functions related to the organization of the stress response in different body tissues are associated with the corticotropin-releasing factor system. This system also plays a relevant role in depression and anxiety disorders, as well as being a direct connection between stress and addiction. A better understanding of how the receptors of this system are regulated would help to expand the understanding of how these receptors respond differently to both drugs and stressful stimuli.
      PubDate: 2022-11-21T12:54:33-08:00
      DOI: 10.1124/molpharm.121.000476
      Issue No: Vol. 102, No. 6 (2022)
       
  • A Sentimental Segue [Editorial]

    • Free pre-print version: Loading...

      Pages: 288 - 289
      PubDate: 2022-11-21T12:54:33-08:00
      DOI: 10.1124/molpharm.122.000632
      Issue No: Vol. 102, No. 6 (2022)
       
  • Correction to "Analgesic {alpha}-Conotoxin Binding Site on the Human GABAB
           Receptor" [ERRATUM]

    • Free pre-print version: Loading...

      Pages: 290 - 290
      PubDate: 2022-11-21T12:54:33-08:00
      DOI: 10.1124/molpharm.122.000543err
      Issue No: Vol. 102, No. 6 (2022)
       
  • Announcement [Editorial]

    • Free pre-print version: Loading...

      Pages: 291 - 291
      PubDate: 2022-11-21T12:54:33-08:00
      DOI: 10.1124/molpharm.122.000635
      Issue No: Vol. 102, No. 6 (2022)
       
 
JournalTOCs
School of Mathematical and Computer Sciences
Heriot-Watt University
Edinburgh, EH14 4AS, UK
Email: journaltocs@hw.ac.uk
Tel: +00 44 (0)131 4513762
 


Your IP address: 3.239.112.140
 
Home (Search)
API
About JournalTOCs
News (blog, publications)
JournalTOCs on Twitter   JournalTOCs on Facebook

JournalTOCs © 2009-