Abstract：
:Several 2-amino-3-benzoylthiophenes were found to increase the binding of [3H]N6-cyclohexyladenosine to A1 adenosine receptors in rat brain membranes. Concentration-response curves were bell-shaped, with up to 45% stimulation of binding at 10 microM followed by inhibition at higher concentrations. Because these compounds originated from a series of nonxanthine adenosine antagonists, the inhibition of binding was attributed to the presence of interfering adenosine antagonist activity. The compounds stimulated binding of several A1 agonist ligands but only inhibited binding of the A1 antagonist ligand [3H]8-cyclopentyl-1,3-dipropylxanthine, indicating that enhancement was specific for the agonist conformation of the receptor. The enhancement was also specific for the A1 receptor, because agonist binding to A2 adenosine, M2 muscarinic, alpha 2 adrenergic, and delta opiate receptors showed little or no enhancement. Uncoupling of the A1 receptor from the inhibitory guanine nucleotide-binding protein did not prevent enhancement. The enhancers slowed the dissociation of [3H]N6-cyclohexyladenosine from the A1 receptor, implying an allosteric mechanism of action. The inhibition of forskolin-stimulated cyclic AMP accumulation in FRTL-5 cells was employed as a functional index of A1 receptor activation. The enhancers caused up to 19-fold leftward shifts in the concentration-response curve for N6-cyclopentyladenosine and also caused up to 55% inhibition of cyclic AMP accumulation in the absence of agonist. The binding and functional results are consistent with a model in which the enhancers bind preferentially to the agonist conformation of the A1 receptor, thereby shifting the receptor equilibrium in favor of agonist binding. Adenosine enhancers may be useful for ischemia and other conditions involving local energy deficits. More generally, allosteric enhancers may provide a means for strengthening physiological control circuits in a variety of receptor systems.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Bruns RF,Fergus JHsubject
Has Abstractpub_date
1990-12-01 00:00:00pages
939-49issue
6eissn
0026-895Xissn
1521-0111journal_volume
38pub_type
杂志文章abstract：:Ca2-dependent protein phosphorylations activated by calmodulin or phospholipid were studied using selective inhibitors. Both protein phosphorylations were inhibited by N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide (W-7) and its derivatives. Kinetic analysis indicated that the primary effect of these agents was me...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1982-09-01 00:00:00
abstract：:Ethanol administration to rats by ethanol vapor inhalation (14 days) results in a 40-50% reduction in the level of gamma-aminobutyric acidA (GABAA) receptor alpha 1 subunit mRNAs [4.4 and 4.8 kilobases (kb)] in the cerebral cortex. The level of alpha 2 subunit mRNA (8.0 kb) was also reduced by 29%, whereas there was n...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1991-02-01 00:00:00
abstract：:Hepatic very-low-density lipoprotein particles (VLDL) containing full-length apolipoprotein B100 are metabolized in the blood stream to low-density lipoprotein (LDL) particles, whose elevated levels increase the risk of atherosclerosis. Statins and bile-acid sequestrants are effective LDL-lowering therapies for many p...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.61.2.269
更新日期：2002-02-01 00:00:00
abstract：:We describe here the cloning and characterization of a rat homolog of the chemokine receptor CXCR3. The predicted amino acid sequence of rat CXCR3 contains 367 amino acid residues, sharing 96 and 87% amino acid sequence identity to the murine and human CXCR3, respectively. Among a large panel of chemokines tested, onl...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：2000-06-01 00:00:00
abstract：:The glucagon-like peptide-1 receptor (GLP-1R) is a key physiological regulator of insulin secretion and a major therapeutic target for the treatment of type II diabetes. However, regulation of GLP-1R function is complex with multiple endogenous peptides that interact with the receptor, including full-length (1-37) and...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.111.072884
更新日期：2011-09-01 00:00:00
abstract：:The level of cellular ceramide, an apoptotic rheostat, is increased by sphingomyelinase or de novo synthesis. The expression of the glutathione S-transferase (GST) gene, whose induction accounts for cell viability, is regulated by activation of CCAAT/enhancer binding protein-beta (C/EBPbeta) and NF-E2-related factor-2...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.65.6.1475
更新日期：2004-06-01 00:00:00
abstract：:The activities of phosphorylase kinase and myosin light-chain kinase are regulated by Ca2+ binding to calmodulin. However, differences in the activation properties of the purified enzymes are apparent, since calmodulin binds to phosphorylase kinase in the absence of Ca2+ whereas prior formation of a Ca2+ . calmodulin ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1983-05-01 00:00:00
abstract：:Diltiazem is a widely prescribed Ca2+ antagonist drug for cardiac arrhythmia, hypertension, and angina pectoris. Using the ancestral CaV channel construct CaVAb as a molecular model for X-ray crystallographic analysis, we show here that diltiazem targets the central cavity of the voltage-gated Ca2+ channel underneath ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.119.117531
更新日期：2019-10-01 00:00:00
abstract：:The role of mobilization of intracellular Ca2+ in the adrenergic-stimulated cAMP accumulation in rat pinealocytes was investigated with thapsigargin, an agent that inhibits endoplasmic reticulum Ca2+-ATPase. It was found that although thapsigargin alone had no effect on the basal cAMP accumulation, it potentiated the ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1996-06-01 00:00:00
abstract：:Prolonged ethanol exposure causes central nervous system hyperexcitability that involves a loss of GABAergic inhibition. We previously demonstrated that long-term ethanol exposure enhances the internalization of synaptic GABA(A) receptors composed of alpha1beta2/3gamma2 subunits. However, the mechanisms of ethanol-med...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.109.063016
更新日期：2010-05-01 00:00:00
abstract：:The decrease in mu-opioid receptor activity after chronic agonist exposure (1 microM [D-Ala(2),N-MePhe(4),Gly-ol(5)]-enkephalin) is largely due to kinase-mediated phosphorylation of intracellular receptor domains. We have recently shown that the substitution of two putative Ca(2+)/calmodulin-dependent protein kinase I...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.58.2.328
更新日期：2000-08-01 00:00:00
abstract：:The seven-transmembrane receptor Smoothened (Smo) is the major component involved in signal transduction of the Hedgehog (Hh) morphogens. Smo inhibitors represent a promising alternative for the treatment of several types of cancers linked to abnormal Hh signaling. Here, on the basis of experimental data, we generated...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.110.065102
更新日期：2010-10-01 00:00:00
abstract：:Hypertriglyceridemia is a frequent complication accompanying the treatment of patients with either retinoids or rexinoids, [retinoid X receptor (RXR)-selective retinoids]. To investigate the cellular and molecular basis for this observation, we have studied the effects of rexinoids on triglyceride metabolism in both n...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.59.2.170
更新日期：2001-02-01 00:00:00
abstract：:Resistance to cisplatin, one of the most widely used anticancer chemotherapeutic agents, is a major clinical problem. There is no effective way to predict development of cisplatin resistance in cancers. As determined by reverse transcription-polymerase chain reaction and Western blotting, the expression of gamma-caten...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.65.5.1217
更新日期：2004-05-01 00:00:00
abstract：:Dehydroepiandrosterone (DHEA) is a peroxisome proliferating agent when administered in pharmacological dosages, but it has not been shown to function through the peroxisome proliferator-activated receptor in cell-based assays. Because members of the thyroid hormone/vitamins A and D nuclear receptor subfamily, includin...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1996-02-01 00:00:00
abstract：:Adaptive changes in gene expression are thought to contribute to dependence, addiction and other behavioral responses to chronic ethanol abuse. DNA array studies provide a nonbiased detection of networks of gene expression changes, allowing insight into functional consequences and mechanisms of such molecular response...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.58.6.1593
更新日期：2000-12-01 00:00:00
abstract：:The efficacy of antineoplastic compounds can depend heavily on the genetic background of the cells exposed to the drugs. This becomes evident by the fact that HT-29 human colon cancer cells but not primary murine nontransformed colonocytes are efficiently submitted to apoptosis by the flavonoid flavone. By determining...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.64.6.1494
更新日期：2003-12-01 00:00:00
abstract：:Prokaryotes produce a variety of toxins that affect genomic function of both eukaryotes and prokaryotes. The 375-base pair bacterial gene Streptoalloteichus hindustanus (Sh) ble encodes a small protein, Streptoalloteichus hindustanus bleomycin resistance protein (BRP), that inhibits in vitro DNA cleavage by the prokar...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1993-12-01 00:00:00
abstract：:K-252b, a member of the staurosporine family of protein kinase inhibitors, selectively potentiates the activation of the nerve growth factor receptor, TrkA, by a nonpreferred ligand, neurotrophin-3 (NT-3), in a variety of cell types. At higher (micromolar) concentrations of K-252b, an inhibitory effect occurs because ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.56.1.185
更新日期：1999-07-01 00:00:00
abstract：:We show here that arsenite (As(3+)) elicits multiple effects on gene control, such as the interruption of cell cycle control by initiating G(2)/M arrest as well as inhibiting the aryl hydrocarbon (Ah) receptor-mediated 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible expression of CYP1A1. This raises the question ...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.104.006130
更新日期：2005-04-01 00:00:00
abstract：:Maurotoxin (MTX) is a potent blocker of human voltage-activated Kv1.2 and intermediate-conductance calcium-activated potassium channels, hIKCa1. Because its blocking affinity on both channels is similar, although the pore region of these channels show only few conserved amino acids, we aimed to characterize the bindin...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.104.002774
更新日期：2004-11-01 00:00:00
abstract：:Controlled inhibition of brain acetyl- and butyrylcholinesterases (AChE and BChE, respectively) and of monoamine oxidase-B (MAO-B) may slow neurodegeneration in Alzheimer's and Parkinson's diseases. It was postulated that certain carbamate esters would inhibit AChE and BChE with the concomitant release in the brain of...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.107.033928
更新日期：2007-06-01 00:00:00
abstract：:Adenosine receptors of the A1 and A2 subtypes were characterized in membranes from DDT1 MF-2 smooth muscle cells. These cells possess a high density of A1 adenosine receptors (Bmax = 0.8-0.9 pmol/mg of protein), as measured by both agonist and antagonist radioligands. Agonists compete for [125I]N6-[2-(4-amino-3-iodoph...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1990-02-01 00:00:00
abstract：:Pharmacological study of rat thalamic gamma-aminobutyric acidA (GABAA) receptors revealed the presence of two distinct populations, namely, diazepam-sensitive and diazepam-insensitive [3H]Ro15-4513 binding sites accounting for 94 +/- 2% (1339 +/- 253 fmol/mg protein) and 6 +/- 2% (90 +/- 44 fmol/mg protein) of total s...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.56.1.110
更新日期：1999-07-01 00:00:00
abstract：:Melanoma differentiation associated gene-7 (mda-7)/interleukin-24 (IL-24), a member of the IL-10 cytokine gene family, preferentially induces cell death in neoplastic epithelial cells types while sparing their normal counterparts. The effects of mda-7/IL-24 in acute myeloid leukemia (AML) cells have not been extensive...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.110.068007
更新日期：2010-12-01 00:00:00
abstract：:Tritiated dextromethorphan ([3H]DM) binds to two distinct sites in guinea pig brain, a high-affinity site (Kd = 13-20 nM) and a low-affinity site (Kd greater than 200 nM). Binding of [3H] DM to the high-affinity site is rapid, reversible, saturable, proportional to tissue concentration, and pH-dependent. The sites hav...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1983-05-01 00:00:00
abstract：:The relations between the single high affinity binding sites for azapropazone, phenylbutazone, chlorpropamide, sulfathiazole, and iophenoxate and the binding regions of human serum albumin represented by the marker ligands diazepam, phenol red, salicylate, and warfarin were examined by a series of competition experime...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1988-08-01 00:00:00
abstract：:The orphan nuclear receptor liver receptor homolog 1 (LRH-1; NR5A2) is a potent regulator of cholesterol metabolism and bile acid homeostasis. Recently, LRH-1 has been shown to play an important role in intestinal inflammation and in the progression of estrogen receptor positive and negative breast cancers and pancrea...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.114.095554
更新日期：2015-02-01 00:00:00
abstract：:Glyceryl trinitrate (GTN) is used in the treatment of angina pectoris and cardiac failure, but the rapid onset of GTN tolerance limits its clinical utility. Research suggests that a principal cause of tolerance is inhibition of an enzyme responsible for the production of physiologically active concentrations of NO fro...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：10.1124/mol.64.5.1109
更新日期：2003-11-01 00:00:00
abstract：:To learn more about the binding conformation of phencyclidine (PCP) and to arrive at analogues of higher affinity, which may serve as noncompetitive N-methyl-D-aspartate receptor antagonists, eight optically pure PCP analogues were designed with the aid of computer. These compounds represent conformationally constrain...
journal_title：Molecular pharmacology
pub_type： 杂志文章
doi：
更新日期：1990-03-01 00:00:00
