Abstract:
:Recent studies from our laboratory have provided evidence that multiple states of the phencyclidine (PCP) receptor exist. In addition, several compounds such as PCP and the novel anticonvulsant MK-801 were found to inhibit binding more potently in the presence of Mg2+ and L-glutamate (L-GLU) than when these agents were excluded from the binding assay. In the present study, a number of pharmacological compounds that have been suggested to interact within the N-methyl-D-aspartate (NMDA) receptor complex, including tricyclic antidepressants (TCAs), were examined for their ability to inhibit the binding of [3H]1-[1-(2-thienyl)cyclohexyl]piperidine [( 3H]TCP) in the absence or presence of Mg2+ and L-GLU. The TCAs imipramine, amitriptyline, and opipramol produced shallow inhibition curves in the absence of Mg2+ and L-GLU. Computer analysis of the binding data indicated that a two-component binding model described the data significantly better than a one-component model. In the presence of Mg2+ and L-GLU, the inhibition curves became steeper and were shifted to the right, and computer analysis of the binding data indicated that a one-component model adequately described the binding data. A series of other centrally active compounds, including several antipsychotics and antihistamines, the antiparkinsonian anticholinergic trihexyphenidyl and the antitussive dextromethorphan, were also found to be affected similarly by the inclusion of Mg2+ and L-GLU in the binding assay. Dextrorphan, in contrast to dextromethorphan, inhibited [3H]TCP binding more potently in the presence of Mg2+ and L-GLU. The present results suggest that the compounds that inhibit binding more potently in the absence of Mg2+ and L-GLU are interacting with the PCP receptor in a different manner from that of PCP and MK-801, because these open-channel blockers inhibit [3H]TCP binding more potently in the presence of Mg2+ and L-GLU. The data support previous findings that TCAs interact with the NMDA receptor complex and suggest that the compounds trihexyphenidyl and dextromethorphan, which have been shown to block NMDA-mediated neurotoxicity, may produce their effects through an interaction with the PCP receptor, albeit by a different mechanism from that of open-channel blockers.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Sills MA,Loo PSsubject
Has Abstractpub_date
1989-07-01 00:00:00pages
160-5issue
1eissn
0026-895Xissn
1521-0111journal_volume
36pub_type
杂志文章abstract::Previous studies have established that two Xbal polymorphic restriction fragments [11.5 and 44 kilobases (kb)] hydridizing to a full length debrisoquin hydroxylase cDNA are associated with two different mutant alleles for the debrisoquin hydroxylase gene (IID6). An independent allele, defined by Xbal 16- and 9-kb frag...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1990-05-01 00:00:00
abstract::Although ATP-sensitive K+ channels continue to be explored for their therapeutic potential, developments in high-affinity radioligands to investigate native and recombinant KATP channels have been less forthcoming. This study reports the identification and pharmacological characterization of a novel iodinated 1,4-dihy...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.64.1.143
更新日期:2003-07-01 00:00:00
abstract::Mouse embryonic spinal cord neurons in culture exhibit spontaneous calcium oscillations from day in vitro (DIV) 6 through DIV 10. Such spontaneous activity in developing spinal cord contributes to maturation of synapses and development of pattern-generating circuits. Here we demonstrate that these calcium oscillations...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.111.071456
更新日期:2011-06-01 00:00:00
abstract::bTREK-1 K(+) channels set the resting membrane potential of bovine adrenal zona fasciculata (AZF) cells and function pivotally in the physiology of cortisol secretion. Adrenocorticotropic hormone controls the function and expression of bTREK-1 channels through signaling mechanisms that may involve cAMP and downstream ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.109.061861
更新日期:2010-03-01 00:00:00
abstract::Celecoxib (CE) is a nonsteroidal anti-inflammatory drug (NSAID) that is a specific inhibitor of cyclooxygenase 2 (COX2). It is indicated for a variety of chronic inflammatory conditions, including rheumatoid arthritis. Over the last few years, adverse cardiovascular effects and increased risk for heart attacks have be...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.105.020669
更新日期:2006-05-01 00:00:00
abstract::Proliferation of activated T cells and CD56 bright natural killer (Cytokine Growth Factor Rev 13:169-183, 1995) cells caused by interleukin-2 (IL-2) has been exploited in IL-2-based therapies for the treatment of metastatic renal cell carcinoma and melanoma (J Clin Oncol 13:688-696, 1995; J Clin Oncol 17: 2105-2116, 1...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.66.4.
更新日期:2004-10-01 00:00:00
abstract::The neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) and their class II G protein-coupled receptors VPAC(1), VPAC(2), and PAC(1) play important roles in human physiology. No small molecule modulator has ever been reported for the VIP/PACAP receptors, and ther...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.109.060137
更新日期:2010-01-01 00:00:00
abstract::Cardiac-directed expression of AC6 has pronounced favorable effects on cardiac function possibly not linked with cAMP production. To determine rigorously whether cAMP generation is required for the beneficial effects of increased AC6 expression, we generated a catalytically inactive AC6 mutant (AC6mut) that has marked...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.110.067298
更新日期:2011-03-01 00:00:00
abstract::Of four monoclonal antibodies to purified rat liver cytochrome P450s, including those from 3-methylcholanthrene-, phenobarbital-, ethanol-, and pregnenolone-16-alpha-carbonitrile-treated rats, only the monoclonal antibody against pregnenolone-16-alpha-carbonitrile-inducible P450 immunodetected proteins in chicken live...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1989-05-01 00:00:00
abstract::N-formyl peptide receptor (FPR1) and N-formyl peptide receptor-like 1 (FPRL1, now known as FPR2) are G protein-coupled receptors involved in host defense and sensing cellular dysfunction. Because of the potential for FPR1/FPR2 as a therapeutic target, our recent high-throughput screening efforts have focused on the id...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.109.060673
更新日期:2010-02-01 00:00:00
abstract::In a previous report we described the use of flunitrazepam as a photoaffinity label to monitor the turnover of the gamma-aminobutyric acid/benzodiazepine receptor complex in primary brain and spinal cord cell cultures [Science (Wash. D. C.) 226:857-860 (1984)]. In the present communication we have extended our studies...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-09-01 00:00:00
abstract::Current evidence suggests that DNA fragmentation plays an integral role in mediating cytotoxicity that results from thymidine nucleotide depletion ("thymineless death"). Recently, Ayusawa et al. [Mutat. Res. 200:221-230 (1988)] reported that dTMP starvation induces cellular processes that result in the release of 50-2...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1991-03-01 00:00:00
abstract::Although much has been learned about the mechanisms of ligand selectivity between different opioid receptor subtypes, little is known about the common opioid binding pocket shared by all opioid receptors. The recently discovered orphanin system offers a good opportunity to study the mechanisms involved in the binding ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.53.4.772
更新日期:1998-04-01 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::Advances in proteomic methodologies based on quantitative mass spectrometry are now transforming pharmacology and experimental biology more broadly. The present review will discuss several examples, based on work in the author's laboratory that focuses on delineating relationships between GPCR signaling and traffickin...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/molpharm.120.000178
更新日期:2020-12-22 00:00:00
abstract::Mutations that inhibit Kv11.1 ion channel activity contribute to abnormalities of cardiac repolarization that can lead to long QT2 (LQT2) cardiac arrhythmias and sudden death. However, for most of these mutations, nothing is known about the molecular mechanism linking Kv11.1 malfunction to cardiac death. We have previ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.112.077966
更新日期:2012-09-01 00:00:00
abstract::Dynamin is a GTPase enzyme involved in membrane constriction and fission during endocytosis. Phospholipid binding via its pleckstrin homology domain maximally stimulates dynamin activity. We developed a series of surface-active small-molecule inhibitors, such as myristyl trimethyl ammonium bromide (MiTMAB) and octadec...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.034207
更新日期:2007-12-01 00:00:00
abstract::Caveolins have been recognized over the past few decades as key regulators of cell physiology. They are ubiquitously expressed and regulate a number of processes that ultimately impact efficiency of cellular processes. Though not critical to life, they are central to stress adaptation in a number of organs. The follow...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.117.111237
更新日期:2018-04-01 00:00:00
abstract::Hepatic CYP2E1 is induced in several models of alcohol administration, but clinically relevant pathology is only observed in rats in a model involving the continuous intragastric administration of an ethanol-containing, corn oil-based, high-fat diet. The level of CYP2E1 correlates with the degree of liver pathology in...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.51.6.944
更新日期:1997-06-01 00:00:00
abstract::The Gαi/o-coupled dopamine D2-like receptor family comprises three subtypes: the D2 receptor (D2R), with short and long isoform variants (D2SR and D2LR), D3 receptor (D3R), and D4 receptor (D4R), with several polymorphic variants. The common overlap of norepinephrine innervation and D2-like receptor expression pattern...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.115.101808
更新日期:2016-04-01 00:00:00
abstract::The nicotinic acetylcholine receptor can be expressed in Xenopus oocytes by injection of in vitro synthesized RNA for the alpha, beta, gamma, and delta mouse muscle subunits. However, detectable responses can also be obtained by injection of alpha, beta, and delta subunit RNA only. The receptors expressed in this case...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1992-04-01 00:00:00
abstract::The lymphocyte potassium channel Kv1.3 is widely regarded as a promising new target for immunosuppression. To identify a potent small-molecule Kv1.3 blocker, we synthesized a series of 5-phenylalkoxypsoralens and tested them by whole-cell patch clamp. The most potent compound of this series, 5-(4-phenylbutoxy)psoralen...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.65.6.1364
更新日期:2004-06-01 00:00:00
abstract::Labeled histidine was taken up into rat leukemic basophil 2H3 cells by a system with high affinity for histidine and then decarboxylated to form histamine. Uptake was partially inhibited and decarboxylation was completely blocked by alpha-fluoromethylhistidine (alpha-FMH) at concentrations of 10-100 microM. alpha-FMH ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1985-08-01 00:00:00
abstract::The ability of dopamine agonists and antagonists to compete with [3H]spiperone binding to rat striatal membrane preparations at 4, 15, 26, and 37 degrees varied markedly with temperature. Dopamine and the dopamine agonist 2-amino-6,7-dihydroxy-1,2,3,4-tetrahydronaphthalene hydrobromide (ADTN) were more potent at lower...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-09-01 00:00:00
abstract::Thiopurine methyltransferase (TPMT) catalyzes the S-methylation of thiopurine drugs such as 6-mercaptopurine. Levels of TPMT activity in human tissue are controlled by a common genetic polymorphism that is an important factor responsible for individual variation in thiopurine drug toxicity and therapeutic efficacy. Ou...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-06-01 00:00:00
abstract::Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are members of the phospholipid growth factor family. A major limitation in the field to date has been a lack of receptor subtype-specific agonists and antagonists. Here, we report that dioctylglycerol pyrophosphate and dioctylphosphatidic acid are selectiv...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:2001-10-01 00:00:00
abstract::A conjugate molecule was synthesized by linking the DNA-intercalative antitumor drug 4'-(9-acridinylamino)methanesulfon-manisidide (mAMSA) via a 4-carboxamide side chain to a dipyrrolecarboxamide moiety structurally related to the minor groove-binding antibiotic netropsin. The molecule (netropsin/ mAMSA) behaves as a ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1997-03-01 00:00:00
abstract::Iodonium inhibition of the flavoenzymes neutrophil NADPH oxidase and cytochrome P450 reductase has been suggested to require reductive metabolism of the inhibitor to a phenyl radical. Inhibition would ultimately result from covalent attachment of phenyl radicals to either the flavin cofactor or adjacent amino acid sid...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-10-01 00:00:00
abstract::We compared the binding of [N-methyl-3H]scopolamine methyl chloride [( 3H]NMS) and pirenzepine to muscarinic receptors in four regions of the rat central nervous system (cortex, hippocampus, striatum, and cerebellum) and in rat heart. Equilibrium binding studies suggested the existence of three classes of receptors: A...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-10-01 00:00:00
abstract::Schizophrenia (SZ), schizoaffective (SZA), and bipolar (BP) disorder are neurodevelopmental psychopathological conditions related, in part, to genetic load and, in part, to environmentally induced epigenetic dysregulation of chromatin structure and function in neocortical GABAergic, glutamatergic, and monoaminergic ne...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.118.113415
更新日期:2019-01-01 00:00:00