Abstract:
:Inhibition of catechol-O-methyltransferase (COMT; EC 2.1.1.6) is a new therapeutic strategy in the treatment of Parkinson's disease. However, nothing is known about the effects of COMT inhibition on levodopa (L-dopa)-induced toxicity in dopamine (DA) neurons. Therefore we evaluated the effects of the selective COMT inhibitors Ro 41-0960, OR-486, and tolcapone alone and in combination with L-dopa in primary mesencephalic cultures from rat. Neither COMT inhibitor affected the growth of tyrosine hydroxylase immunoreactive (THir) cells with concentrations up to 10 microM when studied alone. However, Ro 41-0960 reduced the L-dopa-induced THir cell loss after 24 h in a dose-dependent manner, shifting the TD(50) value from 21 microM in the absence to 71 microM in the presence of 1 microM Ro 41-0960 (P <.01) without affecting survival of non-DA neurons. OR-486 and the clinically used COMT inhibitor tolcapone showed similar effects. In contrast, toxicity induced by D-dopa was not altered by COMT inhibitors. Furthermore, the primary metabolite of L-dopa formed by COMT, 3-O-methyldopa, and the methyl group donor S-adenosyl-L-methionine used by COMT did not alter THir neuron survival and L-dopa-induced toxicity, respectively, with concentrations up to 100 microM. These data demonstrate that COMT inhibition attenuates L-dopa toxicity toward DA neurons in vitro, but probably not by preventing 3-O-methyldopa production or cellular S-adenosyl-L-methionine depletion.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Storch A,Blessing H,Bareiss M,Jankowski S,Ling ZD,Carvey P,Schwarz Jdoi
10.1124/mol.57.3.589keywords:
subject
Has Abstractpub_date
2000-03-01 00:00:00pages
589-94issue
3eissn
0026-895Xissn
1521-0111journal_volume
57pub_type
杂志文章abstract::Magnesium modulates hormone-sensitive adenylate cyclase activation. In the present studies, we have examined the magnesium requirement of beta-adrenergic-stimulated adenylate cyclase activity in permeabilized human lymphocytes. Following isoproterenol pretreatment, under conditions that lead to homologous beta-adrener...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1989-03-01 00:00:00
abstract::Effects of ethanol on the function of Ca(2+)-activated Cl- channels activated by G protein-coupled serotonin (5-hydroxytryptamine, (5-HT)1c) and muscarinic M1 cholinergic receptors were studied in Xenopus oocytes expressing mouse whole-brain mRNA. Ethanol (25-200 mM) inhibited currents evoked by both 5-HT and acetylch...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-05-01 00:00:00
abstract::Human cytochrome P450 (CYP) 2C enzymes metabolize ∼30% of clinically prescribed drugs and various environmental chemicals. CYP2C8, an important member of this subfamily, metabolizes the anticancer drug paclitaxel, certain antidiabetic drugs, and endogenous substrates, including arachidonic acid, to physiologically act...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.115.100255
更新日期:2016-01-01 00:00:00
abstract::The purpose of these studies was to support the hypothesis that an undiscovered cannabinoid receptor exists in brain. [(35)S]GTP gamma S binding was stimulated by anandamide and WIN55212-2 in brain membranes from both CB(1)(+/+) and CB(1)(-/-) mice. In contrast, a wide variety of other compounds that are known to acti...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:2001-07-01 00:00:00
abstract::Computer simulations on a new model of the alpha1b-adrenergic receptor based on the crystal structure of rhodopsin have been combined with experimental mutagenesis to investigate the role of residues in the cytosolic half of helix 6 in receptor activation. Our results support the hypothesis that a salt bridge between ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.61.5.1025
更新日期:2002-05-01 00:00:00
abstract::The nucleoside analogue, 3-deazaadenosine (c3-Ado), serves both as a substrate and as an inhibitor of S-adenosylhomocysteine (AdoHcy) hydrolase, and the ability of this compound to induce accumulation of intracellular AdoHcy and S-3-deazaadenosylhomocysteine (c3-AdoHcy) in various cells and species has been widely doc...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-08-01 00:00:00
abstract::For several GPCRs, discrimination between agonism and antagonism is possible on the basis of thermodynamics parameters, such as binding enthalpy and entropy. In this study, we analyze whether agonists and antagonists can also be discriminated thermodynamically at the histamine H(1) receptor (H(1)R). Because previous s...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.109.055384
更新日期:2009-07-01 00:00:00
abstract::As a member of the transient receptor potential (TRP) ion channel superfamily, the ligand-gated ion channel TRPA1 has been implicated in nociceptive function and pain states. The endogenous ligands that activate TRPA1 remain unknown. However, various agonists have been identified, including environmental irritants (e....
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.033621
更新日期:2007-05-01 00:00:00
abstract::Dantrolene was recently identified as a novel inhibitor of the plasmodial surface anion channel (PSAC), an unusual ion channel on Plasmodium falciparum-infected human red blood cells. Because dantrolene is used clinically, has a high therapeutic index, and has desirable chemical synthetic properties, it may be a lead ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.010553
更新日期:2005-07-01 00:00:00
abstract::We have reported previously that the transmembrane domains of the cholecystokinin-B/gastrin receptor (CCK-BR) comprise a putative ligand binding pocket. In the present study, we examined whether amino acid substitutions within the CCK-BR pocket altered the affinities and/or functional activities of L-365,260 (the prot...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.54.5.857
更新日期:1998-11-01 00:00:00
abstract::The local anesthetic-like Na+ channel-blocking drug [3H]PD85639 [alpha-([4-3H]phenyl)-N-[3-(2,6-dimethyl-1-piperizinyl)-alpha-prop yl] [4-3H]benzeneacetamide] binds specifically to receptor sites on Na+ channels in intact synaptosomes and synaptosomal membranes, purified and reconstituted Na+ channels, and type IIA Na...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-06-01 00:00:00
abstract::The constitutive androstane receptor (CAR) and the pregnane X receptor (PXR) play a major part in the control of drug metabolism and transport. We have previously shown that PXR and CAR expression is controlled by the glucocorticoid receptor (GR) and proposed the existence of a signal transmission cascade GR-(PXR/CAR)...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.105.022046
更新日期:2006-07-01 00:00:00
abstract::Metabotropic glutamate receptor 5 (mGlu5) is a target for the treatment of central nervous system (CNS) disorders, such as schizophrenia and Alzheimer's disease. Furthermore, mGlu5 has been shown to play an important role in hippocampal synaptic plasticity, specifically in long-term depression (LTD) and long-term pote...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.112.082891
更新日期:2013-04-01 00:00:00
abstract::Formyl peptide receptor (FPR) and formyl peptide receptor like 1 (FPRL1) play important roles in inflammation and immunity. Stimulation of FPR and FPRL1 initiates a cascade of signaling events, leading to activation of various phagocyte responses, including chemotaxis, superoxide generation, and exocytosis. Trp-Lys-Ty...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.64.4.841
更新日期:2003-10-01 00:00:00
abstract::Many cellular signaling pathways share regulation by protein phosphatase-2A (PP2A), a widely expressed serine/threonine phosphatase, and the heterotrimeric G protein Galpha(12). PP2A activity is altered in carcinogenesis and in some neurodegenerative diseases. We have identified binding of Galpha(12) with the Aalpha s...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.106.033555
更新日期:2007-05-01 00:00:00
abstract::The intermediate-conductance Ca2+-activated K+ channel (KCa3.1) constitutes an attractive pharmacological target for immunosuppression, fibroproliferative disorders, atherosclerosis, and stroke. However, there currently is no available crystal structure of this medically relevant channel that could be used for structu...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.116.108068
更新日期:2017-04-01 00:00:00
abstract::Recent reports regarding the significance of chemokine receptors in disease have put a spotlight on atypical chemokine receptor 3 (ACKR3). This atypical chemokine receptor is overexpressed in numerous cancer types and has been involved in the modulation of tumor cell proliferation and migration, tumor angiogenesis, or...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.118.115279
更新日期:2019-12-01 00:00:00
abstract::Glucocorticoid-induced tumor necrosis factor receptor-related (GITR) protein is a costimulatory molecule that plays a role in inflammation so that GITR-Fc fusion protein can exert an anti-inflammatory effect. To investigate the mechanism by which GITR-Fc exerts its effects, we first used GITR knock-out (GITR(-/-)) mic...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.044354
更新日期:2008-06-01 00:00:00
abstract::The phenylalkylamine emopamil prevents brain damage due to experimental cerebral ischemia. Stereoselective, high affinity, binding sites for (-)-[3H]emopamil in guinea pig brain cortex and liver membranes have been proposed to mediate its antiischemic effect. Using [N-methyl-3H]LU49888 as a photoaffinity probe we now ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-02-01 00:00:00
abstract::The role of protein kinase C (PKC) in the human aryl hydrocarbon receptor (hAhR) signal transduction pathway was examined in cell lines stably transfected with pGUDLUC6.1, in which luc+ is solely controlled by four dioxin-responsive elements (DREs). These cell lines, P5A11 and HG40/6, were derived from HeLa and HepG2 ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.53.4.691
更新日期:1998-04-01 00:00:00
abstract::Reversible binding of warfarin to defatted serum albumin was studied by equilibrium dialysis at pH 7.4, in a 66 mM sodium phosphate buffer at 37 degrees. The binding isotherm could be described by two stoichiometric binding constants, K1 in the range 141,000 to 192,000 M-1 and K2 at 39,000 to 57,000 M-1. At least two ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1985-02-01 00:00:00
abstract::Mammalian A2-adenosine receptor binding subunits (A2AR) can be visualized by covalent labeling with the photoaffinity crosslinking ligand 125I-2-[4-[2-[2-[(4-aminophenyl)methylcarbonylamino] ethylaminocarbonyl]ethyl]phenyl]ethylamino-5'-N-ethylcarboxamidoad enosine or directly with the azide derivative described in th...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1990-08-01 00:00:00
abstract::Recently, inositol hexakisphosphate (phytic acid) was shown to bind to photoreceptor arrestin and block its interaction with rhodopsin. Such an interaction might predict that inositol polyphosphates could alter G protein-coupled receptor desensitization. To investigate the possible roles of higher inositol polyphospha...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-08-01 00:00:00
abstract::Atropine, the classic muscarinic receptor antagonist, inhibits ion currents mediated by neuronal nicotinic acetylcholine receptors expressed in Xenopus laevis oocytes. At the holding potential of -80 mV, 1 microM atropine inhibits 1 mM acetylcholine-induced inward currents mediated by rat alpha2beta2, alpha2beta4, alp...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.52.5.886
更新日期:1997-11-01 00:00:00
abstract::Rapid activation of guanine nucleotide-binding protein (G protein)-mediated signal transduction mechanisms occurs in many tissues. The human neutrophil provides a useful model for studying the mechanisms of these fast processes. Fluorescent chemotactic tetrapeptide and pentapeptide exhibit 30-50% quenching of fluoresc...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-05-01 00:00:00
abstract::Two forms of the multisubunit gamma-aminobutyric acid (GABA)A receptor were expressed in Xenopus oocytes by injecting mRNA encoding the bovine GABAA receptor subunit cDNAs for alpha 1 beta 1 gamma 2L and alpha 3 beta 1 gamma 2L. The properties of these two combinations were examined by electrophysiological recording o...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-02-01 00:00:00
abstract::A Walker 256 rat carcinoma cell line (WR) has been shown to be resistant to a broad spectrum of bifunctional nitrogen mustards (NM) in cell culture. The parent cell line (WS) from which the WR cells were selected retains marked sensitivity to this class of drugs. Karyotype analysis showed that the parent WS had a chro...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1982-05-01 00:00:00
abstract::One-electron oxidation of several derivatives of pyrazolin-5-one, including the drug antipyrine, were studied by pulse radiolysis of aqueous solutions. All the compounds were found to be oxidized by Br2 rapidly (k approximately 3 X 10(8)-2 X 10(9) M-1 s-1) but considerably more slowly by weaker oxidants, such as perox...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1985-10-01 00:00:00
abstract::Ca-dependent, K-stimulated 86Rb efflux, a measure of Ca-activated K conductance in rat brain synaptosomes, was blocked by phenothiazines and haloperidol. Micromolar concentrations of the phenothiazines, fluphenazine and trifluoperazine, and haloperidol, a non-phenothiazine antipsychotic and calmodulin antagonist, sele...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-02-01 00:00:00
abstract::Tetradecyl 2,3-dihydroxybenzoate (ABG-001) is a lead compound derived from neuritogenic gentisides. In the present study, we investigated the mechanism by which ABG-001 induces neurite outgrowth in a rat adrenal pheochromocytoma cell line (PC12). Inhibitors of insulin-like growth factor 1 (IGF-1) receptor, phosphatidy...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.115.097758
更新日期:2015-08-01 00:00:00