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Molecular Pharmacology

Terry Kenakin
The question of whether signaling bias is a viable discovery strategy for drug therapy is discussed as a value proposition. On the positive side, bias if easily identified and quantified in simple in vitro functional assays with little resource expenditure. However, there are valid pharmacological reasons why these in vitro bias numbers may not accurately translate to in vivo therapeutic systems making the expectation of direct correspondence of in vitro bias to in vivo systems a problematic process. Presently, in vitro bias is used simply as a means to identify unique molecules to be advanced to more complex therapeutic assays but from this standpoint alone, the value proposition lies far to the positive...
January 18, 2018: Molecular Pharmacology
Regine Brox, Lampros Milanos, Noureldin Saleh, Paul Baumeister, Armin Buschauer, Dagmar Hofmann, Markus R Heinrich, Timothy Clark, Nuska Tschammer
Our recent explorations of allosteric modulators (AMs) with improved properties resulted in the identification of two biased negative AMs, N-1-{[3-(4-Ethoxyphenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimi-din2yl]ethyl}-4-(4-fluorobutoxy)-N-[(1-methylpiperidin-4-yl)me-thyl}]butanamide (BD103) and {5-[(N-{1-[3-(4-ethoxyphenyl)-4-oxo-3,4-dihydropyrido[2,3-d]pyrimidin-2-yl]ethyl-2-[4-fluoro-3-(trifluoromethyl)phenyl]acetamido)methyl]-2-fluorophenyl}boronic acid (BD064), that exhibited probe-dependent inhibition of the chemokine receptor CXCR3 signaling...
January 17, 2018: Molecular Pharmacology
Valentin Gorboulev, Saba Rehman, Christoph Michael Albert, Ursula Roth, Marleen Julia Meyer, Mladen Vassielev Tzvetkov, Thomas Dieter Mueller, Hermann Koepsell
Effects of mutations in the modeled outward-open cleft of rat organic cation transporter 1 (rOCT1) on affinities of substrates and inhibitors were investigated. Human embryonic kidney (HEK) 293 cells were stably transfected with rOCT1 or rOCT1 mutants, and uptake of the substrates 1-methyl-4-phenylpyridinium+ (MPP+) and tetraethylammonium+ (TEA+) or inhibition of MPP+ uptake by the non-transported inhibitors tetrabutylammonium+ (TBuA+), tetrapentylammonium+ (TPeA+) and corticosterone was measured. Uptake measurements were performed on confluent cell layers using 2 min-incubation or in dissociated cells using incubation times of 1, 5, or 10 s...
January 16, 2018: Molecular Pharmacology
Rongbao Zhao, Mitra Najmi, Srinivas Aluri, David C Spray, I David Goldman
The proton-coupled folate transporter (PCFT) is ubiquitously expressed in solid tumors where it delivers antifolates, particularly pemetrexed, into cancer cells. Studies on PCFT-mediated transport, to date, have focused exclusively on the influx of folates and antifolates. This paper addresses the impact of PCFT on concentrative transport, critical to the formation of the active polyglutamate congeners, and at pH levels relevant to the tumor microenvironment. A HeLa-derived cell line was employed in which folate-specific transport was mediated exclusively by PCFT...
January 11, 2018: Molecular Pharmacology
Martin C Michel, Steven J Charlton
A single receptor can activate multiple signaling pathways that have distinct or even opposite effects on cell function. Biased agonists selectively stimulate one of these pathways and, therefore, allow a more targeted modulation of cell function and treatment of disease. Dedicated development of biased agonists has led to promising drug candidates in clinical development, such as the G protein-biased μ opioid receptor agonist oliceridine. However, leveraging the theoretic potential of biased agonism for drug discovery faces several challenges...
January 11, 2018: Molecular Pharmacology
Krishna Sriram, Paul A Insel
Estimates vary regarding the number of G protein-coupled receptors, GPCRs, the largest family of membrane receptors that are targeted by approved drugs and the number of such drugs that target GPCRs. We review current knowledge regarding GPCRs as drug targets by integrating data from public databases (CHEMBL, IUPHAR and DRUGBANK) and from the Broad drug repurposing initiative. To account for discrepancies among these sources, we curated a list of GPCRs currently targeted by approved drugs. As of November, 2017, 134 GPCRs are targets for drugs approved in the United States or European Union; 128 GPCRs are targets for drugs listed in the FDA orange book...
January 3, 2018: Molecular Pharmacology
Carlos Coriano, Fabao Liu, Chelsie Sievers, Muxuan Liang, Yidan Wang, Yoongho Lim, Menggang Yu, Wei Xu
The biological effects of estrogens are transduced by two estrogen receptors (ERs), ERα and ERβ, which function in dimer forms. The ERα/α homodimer promotes and the ERβ/β inhibits estrogen dependent growth of mammary epithelial cells, the functions of ERα/β heterodimers remain elusive. Using compounds that promote ERα/β heterodimerization, we have shown that ERα/β heterodimers appeared to inhibit tumor cell growth and migration in vitro. Further dissection of ERα/β heterodimer functions was hampered by the lack of ERα/β heterodimer specific ligands...
January 2, 2018: Molecular Pharmacology
Jayne Gilbert, Geoffry N De Iuliis, Mark Tarleton, Adam McCluskey, Jennette A Sakoff
We have previously reported the synthesis and breast cancer selectivity of (Z)-2-(3,4-dichlorophenyl)-3-(1H-pyrrol-2-yl)acrylonitrile (ANI-7) in cancer cell lines. To further evaluate the selectivity of ANI-7 we have expanded upon the initial cell line panel to now include the breast cancer cell lines (MCF7, MCF7/VP16, BT474, T47D, ZR-75-1, SKBR3, MDA-MB-468, BT20, MDA-MB-231), normal breast cells (MCF-10A) and cell lines derived from colon (HT29), ovarian (A2780), lung (H460), skin (A431), neuronal (BE2C), glial (U87, SJG2), and pancreatic (MIA) cancers...
December 21, 2017: Molecular Pharmacology
Thomas Maxwell Kaiser, Steven A Kell, Hirofumi Kusumoto, Gil Shaulsky, Subhrajit Bhattacharya, Matthew P Epplin, Katie L Strong, Eric J Miller, Bryan D Cox, David S Menaldino, Dennis C Liotta, Stephen F Traynelis, Pieter Buys Burger
NMDA receptors are ligand-gated, cation-selective channels that mediate a slow component of excitatory synaptic transmission. Subunit-selective positive allosteric modulators of NMDA receptor function have therapeutically-relevant effects on multiple processes in the brain. A series of pyrrolidinones, such as PYD-106, that selectively potentiate NMDA receptors that contain the GluN2C subunit have structural determinants of activity that reside between the GluN2C amino terminal domain and the GluN2C agonist binding domain, suggesting a unique site of action...
December 14, 2017: Molecular Pharmacology
Saketh S Dinavahi, Mohammed A Noory, Raghavendra Gowda, Joseph J Drabick, Rogerio I Neves, Arthur Berg, Gavin P Robertson
Drug combinations acting synergistically to kill cancer cells have become increasingly important in melanoma as an approach to manage the recurrent resistant disease. AKT is a major target in this disease but its inhibitors are not effective clinically, which is a major concern. Targeting AKT in combination with WEE1 seems to have potential to make AKT based therapeutics effective clinically. Since agents targeting AKT and WEE1 have been tested individually in the clinic, the quickest way to move the drug combination to patients would be to combine them sequentially, enabling the use of existing phase-I clinical trial toxicity data...
December 14, 2017: Molecular Pharmacology
Peilan Zhou, Jiebing Jiang, Hui Yan, Yulei Li, Junru Zhao, Xiao Wang, Ruibin Su, Zehui Gong
The μ-opioid receptor (MOR) is a Gi/o protein-coupled receptor that mediates analgesic, euphoric, and reward effects. Using a bacterial two-hybrid screen, we reported that the carboxyl tail of the rat MOR associates with A20-binding inhibitor of nuclear factor (NF)-κB (ABIN-1) (Zhou et al., 2015). This interaction was confirmed by direct protein - protein binding and co-immunoprecipitation of MOR and ABIN-1 proteins in cell lysates. Saturation binding studies showed that ABIN-1 had no effect on MOR binding...
December 13, 2017: Molecular Pharmacology
Kathryn E Livingston, M Alexander Stanczyk, Neil Burford, Andrew Alt, Merixtell Canals, John R Traynor
Allosteric modulators of G protein-coupled receptors (GPCRs), including opioid receptors, have been proposed as possible therapeutic agents with enhanced selectivity. BMS-986122 is a positive allosteric modulator (PAM) of the mu-opioid receptor (μ-OR). BMS-986187 is a structurally distinct PAM for the delta-opioid receptor (δ-OR) that has been reported to show 100-fold selectivity in promoting δ-OR over μ-OR agonism. Here we use ligand binding and second messenger assays to show that BMS-986187 is actually an effective PAM at μ-OR and at the kappa opioid receptor (κ-OR), but is ineffective at the nociceptin receptor (NOPR)...
December 12, 2017: Molecular Pharmacology
Timothy B Johnstone, Shailesh R Agarwal, Robert D Harvey, Rennolds S Ostrom
It is widely accepted that cAMP signaling is compartmentalized within cells. However, our knowledge of how receptors, cAMP signaling enzymes, effectors and other key proteins form specific signaling complexes to regulate specific cell responses is limited. The multi-component nature of these systems and the spatiotemporal dynamics involved as proteins interact and move within a cell, make cAMP responses highly complex. Adenylyl cyclases, the enzymatic source of cAMP production, are key starting points for understanding cAMP compartments and defining the functional signaling complexes...
December 7, 2017: Molecular Pharmacology
Magdalena Birker-Robaczewska, Martin Bolli, Markus Rey, Ruben de Kanter, Christopher Kohl, Cyrille Lescop, Maxime Boucher, Sylvie Poirey, Beat Steiner, Oliver Nayler
S1P1 (sphingosine-1-phosphate receptor 1) agonists prevent lymphocyte egress from secondary lymphoid organs and cause a reduction of the number of circulating blood lymphocytes. We hypothesized that S1P1 receptor modulators with pathway-selective signaling properties could help to further elucidate molecular mechanisms involved in lymphocyte trapping. A proprietary S1P1 receptor modulator library was screened for compounds with clear potency differences in β-arrestin recruitment and Gαi protein-mediated signaling...
December 4, 2017: Molecular Pharmacology
Joseph Newcombe, Anna Chatzidaki, Tom D Sheppard, Maya Topf, Neil S Millar
By combining electrophysiological and computational approaches we have examined a series of positive allosteric modulators (PAMs) acting on the human α7 nicotinic acetylcholine receptor (nAChR). Electrophysiological studies have focussed on three α7-selective PAMs (A-867744, TBS-516 and TQS) that display similar effects on wild-type α7 nAChRs. In addition to potentiating agonist-evoked responses, all three compounds reduce receptor desensitisation and, consequently, are classed as type II PAMs. Despite having similar effects on wild-type receptors, A-867744 was found to have profoundly differing effects to TBS-516 and TQS on mutated receptors, a finding that is consistent with previous studies indicating that A-867744 may have a different mechanism of action to other α7-selective type II PAMs...
December 1, 2017: Molecular Pharmacology
Morrie Lam, Natalia Mast, Irina Pikuleva
Cytochrome P450 27A1 (CYP27A1) is a ubiquitous enzyme that hydroxylates cholesterol and other sterols. Complete CYP27A1 deficiency due to genetic mutations is detrimental to human health, whereas 50% of activity retention is not and does not affect the whole body cholesterol levels. CYP27A1 is considered as a potential therapeutic target in breast cancer and age-related neurodegenerative diseases; however CYP27A1 inhibition should be 50%. Herein, 131 pharmaceuticals were tested for their effect on CYP27A1-mediated cholesterol 27-hydroxylation by in vitro enzyme assay...
November 30, 2017: Molecular Pharmacology
Xiaoyan Lin, Amey S Dhopeshwarkar, Megan Huibregtse, Ken Mackie, Andrea G Hohmann
The CB2 cannabinoid agonist LY2828360 lacked both toxicity and efficacy in a clinical trial for osteoarthritis. Whether LY2828360 suppresses neuropathic pain has not been reported and its signaling profile is unknown. In vitro, LY2828360 was a slowly acting but efficacious G protein-biased CB2 agonist, inhibiting cAMP accumulation and activating ERK1/2 signaling while failing to recruit arrestin, activate inositol phosphate signaling or internalize CB2 receptors. In wildtype (WT) mice, LY2828360 (3 mg/kg/day i...
November 30, 2017: Molecular Pharmacology
Daniel J Shin, Allison L Germann, Alexander D Johnson, Stuart A Forman, Joseph H Steinbach, Gustav Akk
GABAA receptors can be directly activated and potentiated by the intravenous anesthetic propofol. Previous photolabeling, modeling and functional data have identified two binding domains through which propofol acts on the GABAA receptor. These domains are defined by the β(M286) residue at the β"+" - α"-" interface in the transmembrane region and the β(Y143) residue near the β"-" surface in the junction between the extracellular and transmembrane domains. In the ternary receptor there are predicted to be 2 copies of each class of sites, for a total of 4 sites per receptor...
November 30, 2017: Molecular Pharmacology
Yi Lu, Weili Zheng, Shengchen Lin, Fusheng Guo, Yanlin Zhu, Yijuan Wei, Xi Liu, Shikai Jin, Lihua Jin, Yong Li
Farnesoid X receptor (FXR) and G-protein-coupled BA receptor 1 (GPBAR1) are two important bile acid (BA) receptors. As a non-BAs drug template for GPBAR1, none of the natural oleanane-type triterpene has been reported as FXR ligands, despite that FXR and GPBAR1 have similar binding pockets for BAs. Here, we report the natural triterpene hedragonic acid that has been isolated from the stem and root of Celastrus orbiculatus Thunb. (COT) as an effective agonist for FXR. Both biochemical AlphaScreen and cell-based reporter assays showed that hedragonic acid regulated the transcriptional activity of FXR...
November 21, 2017: Molecular Pharmacology
Gustav Akk, Daniel J Shin, Allison L Germann, Joseph H Steinbach
The concerted transition model for multimeric proteins is a simple formulation for analyzing the behavior of transmitter-gated ion channels. Here, we use the model to examine the relationship between the EC50 for activation of the GABAA receptor by the transmitter GABA and basal activity employing concatemeric ternary GABAA receptors expressed in Xenopus oocytes. The basal activity reflects receptor function in the absence of transmitter, and can be changed either by mutation to increase constitutive activity, or by addition of a second agonist (acting at a different site) to increase background activity...
November 17, 2017: Molecular Pharmacology
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