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Molecular Pharmacology

Ee Von Moo, Patrick M Sexton, Arthur Christopoulos, Celine Valant
Muscarinic acetylcholine receptors (mAChRs) are exemplar models for understanding G protein-coupled receptor (GPCR) allostery, possessing a "common" allosteric site in an extracellular vestibule (ECV) for synthetic modulators including gallamine, strychnine and brucine. In addition, there is intriguing evidence of endogenous peptides/proteins that may target this region at the M2 mAChR. A common feature of synthetic and endogenous M2 mAChR negative allosteric modulators (NAMs) is their cationic nature...
September 13, 2018: Molecular Pharmacology
Zhiqiang Hu, Zhilin Wu, Jie Gao, Qi Jia, Na Li, Yeling Ouyang, Shanglong Yao, Xiangdong Chen
Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels were reported to express in the well-known vasomotor region, rostral ventrolateral medulla (RVLM), and inhibited by propofol at clinically relevant concentrations. However, whether HCN channels in RVLM contribute to propofol-induced cardiovascular depression remains unclear. We recorded the hemodynamic changes when either continuous intravenous infusions or microinjections of propofol and ZD-7288 (HCN channels blocker) in RVLM. Difference in the expressions of HCN channels in RVLM neurons of mice of different ages were examined by qRT-PCR, western blotting...
September 7, 2018: Molecular Pharmacology
Ariel Kwaka, Mohammad H Khatami, Joshua Foster, Everett Cochrane, Sarah A Habibi, Hendrick W de Haan, Sean G Forrester
Nematodes exhibit a vast array of cys-loop ligand-gated ion channels with unique pharmacological characteristics. However, many of the structural components that govern the binding of various ligands are unknown. The nematode cys-loop GABA receptor UNC-49 is an important receptor found at neuromuscular junctions, and plays an important role in the sinusoidal movement of worms. The unique pharmacology of this receptor suggests that there are structural differences in the agonist binding site when compared to mammalian receptors...
September 7, 2018: Molecular Pharmacology
Ornella Turani, Guillermina Hernando, Jeremias Corradi, Cecilia Bouzat
Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels involved in neuromuscular transmission. In nematodes, muscle nAChRs are targets of antiparasitic drugs. Bephenium is an anthelmintic compound whose molecular action at the free-living nematode Caenorhabditis elegans , which is a model for anthelmintic drug discovery, is poorly known. We explored its effect on C. elegans locomotion and applied single-channel recordings to identify its molecular target, mechanism of action, and selectivity between mammalian and C...
September 6, 2018: Molecular Pharmacology
Sean T Campbell, Caroline E Franks, Adam L Borne, Myungsun Shin, Liuzhi Zhang, Ku-Lung Hsu
Ritanserin was tested in the clinic as a serotonin receptor inverse agonist but recently emerged as a novel kinase inhibitor with potential applications in cancer. Here, we discovered that ritanserin induced apoptotic cell death of non-small cell and small cell lung cancer (NSCLC, SCLC) cells via a serotonin-independent mechanism. We used quantitative chemical proteomics to reveal a ritanserin-dependent kinase network that includes key mediators of lipid (DGKα, PI4KB) and protein signaling (FER, RAF), metabolism (EF2K, E2AK4), and DNA damage response (TLK2) to broadly kill lung tumor cell types...
August 29, 2018: Molecular Pharmacology
Chongyang Han, Andreas C Themistocleous, Mark Estacion, Fadia B Dib-Hajj, Iulia Blesneac, Lawrence Macala, Carl Fratter, David L Bennett, Stephen G Waxman, Sulayman D Dib-Hajj
Neuropathic pain in patients carrying sodium channel gain-of-function mutations is generally refractory to pharmacotherapy. However, we have shown that clinically-achievable concentration of carbamazepine (CBZ, 30 μM) depolarizes activation in some NaV1.7 mutations such as S241T, a novel CBZ mode-of-action of this drug. CBZ reduces the excitability of dorsal root ganglion (DRG) neurons expressing NaV1.7-S241T mutant channels, and individuals carrying the S241T mutation respond to treatment with CBZ. Whether the novel activation-modulating activity of carbamazepine is specific to NaV1...
August 22, 2018: Molecular Pharmacology
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October 2018: Molecular Pharmacology
Keshav Karki, Sneha Harishchandra, Stephen Safe
Bortezomib alone and in combination with other anticancer agents are extensively used for chemotherapeutic treatment of multiple myeloma (MM) patients and are being developed for treating other cancers. Bortezomib acts through multiple pathways, and in this study with ANBL-6 and RPMI 8226 MM cells we show that bortezomib inhibited growth and induced apoptosis and that this was accompanied by downregulation of specificity protein (Sp) 1, Sp3, and Sp4 transcription factors that are overexpressed in these cells...
October 2018: Molecular Pharmacology
Diana Lupu, Mukesh K Varshney, Daniel Mucs, José Inzunza, Ulf Norinder, Felicia Loghin, Ivan Nalvarte, Joëlle Rüegg
Recent meta-analyses found an association between prenatal exposure to the antidepressant fluoxetine (FLX) and an increased risk of autism in children. This developmental disorder has been related to dysfunctions in the brains' rewards circuitry, which, in turn, has been linked to dysfunctions in dopaminergic (DA) signaling. The present study investigated if FLX affects processes involved in dopaminergic neuronal differentiation. Mouse neuronal precursors were differentiated into midbrain dopaminergic precursor cells (mDPCs) and concomitantly exposed to clinically relevant doses of FLX...
October 2018: Molecular Pharmacology
Xushan Wang, Beverly A Heinz, Yue-Wei Qian, Joan H Carter, Robert A Gadski, Lisa S Beavers, Sheila P Little, Charles R Yang, James P Beck, Junliang Hao, John M Schaus, Kjell A Svensson, Robert F Bruns
The binding site for DETQ [2-(2,6-dichlorophenyl)-1-((1 S ,3 R )-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1 H )-yl)ethan-1-one], a positive allosteric modulator (PAM) of the dopamine D1 receptor, was identified and compared with the binding site for CID 2886111 [ N -(6- tert -butyl-3-carbamoyl-4,5,6,7-tetrahydro-1-benzothiophen-2-yl)pyridine-4-carboxamide], a reference D1 PAM. From D1/D5 chimeras, the site responsible for potentiation by DETQ of the increase in cAMP in response to dopamine was narrowed down to the N-terminal intracellular quadrant of the receptor; arginine-130 in intracellular loop 2 (IC2) was then identified as a critical amino acid based on a human/rat species difference...
October 2018: Molecular Pharmacology
Katriana A Popichak, Sean L Hammond, Julie A Moreno, Maryam F Afzali, Donald S Backos, Richard D Slayden, Stephen Safe, Ronald B Tjalkens
Inflammatory activation of glial cells promotes loss of dopaminergic neurons in Parkinson disease. The transcription factor nuclear factor κB (NF- κ B) regulates the expression of multiple neuroinflammatory cytokines and chemokines in activated glial cells that are damaging to neurons. Thus, inhibition of NF- κ B signaling in glial cells could be a promising therapeutic strategy for the prevention of neuroinflammatory injury. Nuclear orphan receptors in the NR4A family, including NR4A1 (Nur77) and NR4A2 (Nurr1), can inhibit the inflammatory effects of NF- κ B, but no approved drugs target these receptors...
October 2018: Molecular Pharmacology
Xiao-Ying Sun, Li-Lan Sun, Hang Qi, Qin Gao, Gong-Xin Wang, Ning-Ning Wei, KeWei Wang
Coumarin osthole is a dominant bioactive ingredient of the natural Cnidium monnieri plant commonly used for traditional Chinese herbal medicines for therapies and treatments including antipruritus and antidermatitis. However, the molecular mechanism underlying the action of osthole remains unclear. In this study, we report that osthole exerts an antipruritic effect through selective inhibition of Ca2+ -permeable and thermosensitive transient receptor potential vanilloid 3 (TRPV3) cation channels that are primarily expressed in the keratinocytes of the skin...
October 2018: Molecular Pharmacology
Tyler S Beyett, Xinmin Gan, Shannon M Reilly, Louise Chang, Andrew V Gomez, Alan R Saltiel, Hollis D Showalter, John J G Tesmer
Chronic low-grade inflammation is a hallmark of obesity, which is a risk factor for the development of type 2 diabetes. The drug amlexanox inhibits I κ B kinase ε (IKK ε ) and TANK binding kinase 1 (TBK1) to promote energy expenditure and improve insulin sensitivity. Clinical studies have demonstrated efficacy in a subset of diabetic patients with underlying adipose tissue inflammation, albeit with moderate potency, necessitating the need for improved analogs. Herein we report crystal structures of TBK1 in complex with amlexanox and a series of analogs that modify its carboxylic acid moiety...
October 2018: Molecular Pharmacology
Kathryn D Luderman, Jennie L Conroy, R Benjamin Free, Noel Southall, Marc Ferrer, Marta Sanchez-Soto, Amy E Moritz, Blair K A Willette, Tim J Fyfe, Prashi Jain, Steve Titus, Lisa A Hazelwood, Jeffrey Aubé, J Robert Lane, Kevin J Frankowski, David R Sibley
The D1 dopamine receptor is linked to a variety of neuropsychiatric disorders and represents an attractive drug target for the enhancement of cognition in schizophrenia, Alzheimer disease, and other disorders. Positive allosteric modulators (PAMs), with their potential for greater selectivity and larger therapeutic windows, may represent a viable drug development strategy, as orthosteric D1 receptor agonists possess known clinical liabilities. We discovered two structurally distinct D1 receptor PAMs, MLS6585 and MLS1082, via a high-throughput screen of the NIH Molecular Libraries program small-molecule library...
October 2018: Molecular Pharmacology
Mohammed Alqinyah, Faris Almutairi, Menbere Y Wendimu, Shelley B Hooks
The small regulator of G protein signaling protein RGS10 is a key regulator of neuroinflammation and ovarian cancer cell survival; however, the mechanism for RGS10 function in these cells is unknown and has not been linked to specific G protein pathways. RGS10 is highly enriched in microglia, and loss of RGS10 expression in microglia amplifies production of the inflammatory cytokine tumor necrosis factor α (TNF α ) and enhances microglia-induced neurotoxicity. RGS10 also regulates cell survival and chemoresistance of ovarian cancer cells...
October 2018: Molecular Pharmacology
Wojciech G Garbacz, Hirdesh Uppal, Jiong Yan, Meishu Xu, Songrong Ren, Donna B Stolz, Min Huang, Wen Xie
Cholesterol is essential for numerous biologic functions and processes, but an excess of intracellular cholesterol can be toxic. Intestinal cholesterol absorption is a major determinant of plasma cholesterol level. The liver X receptor (LXR) is a nuclear receptor known for its activity in cholesterol efflux and reverse cholesterol transport. In this study, we uncovered a surprising function of LXR in intestinal cholesterol absorption and toxicity. Genetic or pharmacologic activation of LXR α -sensitized mice to a high-cholesterol diet (HCD) induced intestinal toxicity and tissue damage, including the disruption of enterocyte tight junctions, whereas the same HCD caused little toxicity in the absence of LXR activation...
October 2018: Molecular Pharmacology
Rían W Manville, Geoffrey W Abbott
Synthetic gabapentinoids, exemplified by gapapentin and pregabalin, are in extensive clinical use for indications including epilepsy, neuropathic pain, anxiety, and alcohol withdrawal. Their mechanisms of action are incompletely understood, but are thought to involve inhibition of α 2 δ subunit-containing voltage-gated calcium channels. Here, we report that gabapentin is a potent activator of the heteromeric KCNQ2/3 voltage-gated potassium channel, the primary molecular correlate of the neuronal M-current, and also homomeric KCNQ3 and KCNQ5 channels...
October 2018: Molecular Pharmacology
Songqi Gao, Tanu Parmar, Grazyna Palczewska, Zhiqian Dong, Marcin Golczak, Krzysztof Palczewski, Beata Jastrzebska
Continuous regeneration of the 11- cis -retinal visual chromophore from all- trans -retinal is critical for vision. Insufficiency of 11- cis -retinal arising from the dysfunction of key proteins involved in its regeneration can impair retinal health, ultimately leading to loss of human sight. Delayed recovery of visual sensitivity and night blindness caused by inadequate regeneration of the visual pigment rhodopsin are typical early signs of this condition. Excessive concentrations of unliganded, constitutively active opsin and increased levels of all- trans -retinal and its byproducts in photoreceptors also accelerate retinal degeneration after light exposure...
October 2018: Molecular Pharmacology
Nora Lee, Mary F Hebert, David J Wagner, Thomas R Easterling, C Jason Liang, Kenneth Rice, Joanne Wang
Metformin, an oral antihyperglycemic, is increasingly being prescribed to pregnant women with gestational diabetes. Metformin is a hydrophilic cation and relies on organic cation transporters to move across cell membranes. We previously demonstrated that human and mouse placentas predominantly express organic cation transporter 3 (OCT3), but the impact of this transporter on maternal and fetal disposition of metformin is unknown. Using immunofluorescence colocalization studies in term human placenta, we showed that OCT3 is localized to the basal (fetal-facing) membrane of syncytiotrophoblast cells with no expression on the apical (maternal-facing) membrane...
October 2018: Molecular Pharmacology
Melissa Reiners, Michael A Margreiter, Adrienne Oslender-Bujotzek, Giulia Rossetti, Stefan Gründer, Axel Schmidt
Acid-sensing ion channel 3 (ASIC3) is a proton-gated Na+ channel with important roles in pain. ASIC3 quickly desensitizes in less than a second, limiting its capacity to sense sustained acidosis during pain. RFamide neuropeptides are modulators of ASIC3 that slow its desensitization and induce a variable sustained current. The molecular mechanism of slowed desensitization and the RFamide binding site on ASIC3 are unknown. RPRFamide, a RFamide from the venom of a cone snail, has a comparatively high affinity for ASIC3 and strongly slows its desensitization...
October 2018: Molecular Pharmacology
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