Abstract:
:Barbiturate-induced anesthesia is a complex mechanism that probably involves several ligand-gated ion channel superfamilies. One of these superfamilies includes the archetypical nicotinic acetylcholine receptor (nAChR), in which barbiturates act as noncompetitive antagonists. In this regard, we used the Torpedo californica nAChR and a series of barbiturate analogs to characterize the barbiturate binding site(s) on this superfamily member. [(14)C]Amobarbital binds to one high-affinity (K(d) = 3.7 microM) and several (approximately 11) low-affinity (K(d) = 930 microM) sites on the resting and desensitized nAChRs, respectively. Characteristics of the barbiturate binding site on the resting nAChR include: (1) a tight structure-activity relationship. For example, the barbiturate isobarbital [5-ethyl-5'-(2-methylbutyl) barbituric acid] is >10-fold less potent than its formula isomer amobarbital [5-ethyl-5'-(3-methylbutyl) barbituric acid] in inhibiting [(14)C]amobarbital binding. (2) A binding locus within the pore of the nAChR ion channel. Each of the barbiturate analogs inhibited the binding of [(3)H]tetracaine or photoincorporation of 3-trifluoromethyl-3-(m-[(125)I]iodophenyl) diazirine in a mutually exclusive manner. (3) Stereoselective binding. The R(+)-enantiomers of isobarbital and pentobarbital are approximately 2-fold more potent in inhibiting 3-trifluoromethyl-3-(m-[(125)I]iodophenyl) diazirine photoincorporation than the S(-)-enantiomers. Finally, molecular modeling suggests that within the channel, the pyrimidine ring of the barbiturate is located just above the highly conserved leucine ring (M2--9; e.g., delta Leu-265), whereas the 5' side chain projects downward, and depending upon its conformation, introduces steric hindrance to binding because of the restriction in the lumen of the channel introduced by the leucine side chains.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Arias HR,McCardy EA,Gallagher MJ,Blanton MPkeywords:
subject
Has Abstractpub_date
2001-09-01 00:00:00pages
497-506issue
3eissn
0026-895Xissn
1521-0111journal_volume
60pub_type
杂志文章abstract::GABAA receptors are predominantly composed of alphabetagamma and alphabetadelta isoforms in the brain. It has been proposed that alphabetagamma receptors mediate phasic inhibition, whereas alphabetadelta receptors mediate tonic inhibition. Propofol (2,6-di-isopropylphenol), a widely used anesthetic drug, exerts its ef...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.003426
更新日期:2004-12-01 00:00:00
abstract::At central excitatory synapses, the transient elevation of intracellular calcium reduces N-methyl-D-aspartate (NMDA) receptor activity. Such 'calcium-dependent inactivation' is mediated by interactions of calcium/calmodulin and alpha-actinin with the C terminus of NMDA receptor 1 (NR1) subunit. However, inactivation i...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.61.3.595
更新日期:2002-03-01 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::Two peptides, which have no significant homology with known protein structures, were obtained by microsequencing of a mu-opioid binding protein purified to homogeneity from bovine striatal membranes. Polyclonal antibodies generated against portions of these peptides immunoprecipitated up to 65% of radiolabeled purifie...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-10-01 00:00:00
abstract::A collection of analogues of atrial natriuretic peptide (ANP) were screened for their ability to inhibit ANP-induced cGMP stimulation. The antagonists revealed through this screen are structurally related; almost all are substituted at either aspartate-13 or phenylalanine-26. This tendency is consistent throughout sev...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1990-12-01 00:00:00
abstract::Cell-penetrating peptides are amphipathic or cationic oligopeptides able to transport covalently attached cargoes across cell membranes. Peptide aptamers are polypeptide fragments of endogenous proteins that mimic and thus perturb interactions with other cellular proteins. Combining aptamer and CPP technology can gene...
journal_title:Molecular pharmacology
pub_type: 评论,杂志文章
doi:10.1124/mol.105.011429
更新日期:2005-04-01 00:00:00
abstract::Acetylsalicylic acid (aspirin) is a cyclooxygenase (COX) inhibitor, yet some of its therapeutic effects are thought to derive from mechanisms unrelated to prostaglandin synthesis inhibition. In human intestinal myofibroblasts, aspirin, at therapeutic doses, had the unexpected effect of inducing prolonged COX-2 express...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.65.2.470
更新日期:2004-02-01 00:00:00
abstract::The induction of human inducible nitric-oxide synthase (iNOS) expression depends (among other factors) on activation of the signal transducer and activator of transcription 1 (STAT1) pathway. Therefore, the STAT1 pathway may be an appropriate target for the development of inhibitors of iNOS expression. HeLa S3 cells t...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.63.2.383
更新日期:2003-02-01 00:00:00
abstract::The isoprenoid donor for protein geranylgeranylation reactions, geranylgeranyl diphosphate (GGDP), is the product of the enzyme GGDP synthase (GGDPS) that condenses farnesyl diphosphate (FDP) and isopentenyl pyrophosphate. GGDPS inhibition is of interest from a therapeutic perspective for multiple myeloma because we h...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.116.107326
更新日期:2017-03-01 00:00:00
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 in...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.57.3.589
更新日期:2000-03-01 00:00:00
abstract::Nicotine biotransformation affects the smoking habits of addicted individuals and therefore their health risk. Using an improved analytical method, we have discovered that the human UDP-glucuronosyltransferase (UGT) 2B10, a liver enzyme previously unknown to conjugate nicotine or exhibit considerable activity toward a...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.107.037093
更新日期:2007-09-01 00:00:00
abstract::Membrane trafficking of the δ-opioid receptor (DOR) from intracellular compartments to plasma membrane in central neurons, induced by various pathological conditions such as long-term opioid exposure, represents unique receptor plasticity involved in the mechanisms of long-term opioid effects in opioid addiction and o...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.111.076307
更新日期:2012-03-01 00:00:00
abstract::4-PIOL is a structural analog of GABA that has low efficacy at GABAA receptor CI- channels and activates a nondesensitizing CI- conductance in central neurons. We investigated the biophysical mechanisms of its low efficacy in embryonic olfactory bulb neurons, which express a limited number of GABAA receptor subunit tr...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1995-08-01 00:00:00
abstract::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 multicomponent nature of these systems and the spatiotemp...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.117.110825
更新日期:2018-04-01 00:00:00
abstract::The binding of two anthranilic acid derivatives, glafenic and floctafenic acids, to human erythrocytes and plasma proteins has been investigated in vitro by equilibrium dialysis. Despite their close chemical structures it was shown that the binding of the two compounds to serum albumin, lipoproteins, and erythrocytes ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1987-03-01 00:00:00
abstract::PC-12 cells, derived from a rat pheochromocytoma, were found to take up tritiated serotonin ([3H]5-HT) from the external medium by means of a saturable mechanism which follows Michaelis-Menten kinetics. The apparent Km of uptake was 0.39 microM and the Vmax was 0.40 pmole/min/10(6) cells. The uptake was temperature-de...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1982-03-01 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::Molecular cloning of the alpha 2A-adrenergic receptor has shown that this receptor is a member of the gene superfamily of guanine nucleotide-binding protein (G protein)-coupled receptors. The alpha 2A-adrenergic receptor expressed in Chinese hamster ovary (CHO) cells attenuates and potentiates forskolin-stimulated cAM...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1991-08-01 00:00:00
abstract::Rat and human lung microsomal cytochrome P-450 (P-450) enzymes have been characterized with regard to their catalytic activities towards several xenobiotic chemicals, including procarcinogens, in different microsomal preparations. Rat lung microsomal P-450s were more active than the human P-450s in catalyzing most of ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1992-05-01 00:00:00
abstract::Exchange protein directly activated by cAMP (EPAC) and cAMP-dependent protein kinase (PKA) are two intracellular receptors that mediate the effects of the prototypic second messenger cAMP. Identifying pharmacological probes for selectively modulating EPAC activity represents a significant unmet need within the researc...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.112.080689
更新日期:2013-01-01 00:00:00
abstract::High-throughput screening has led to the identification of small-molecule blockers of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel, but the structural basis of blocker binding remains to be defined. We developed molecular models of the CFTR channel on the basis of homology to the bac...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.112.080267
更新日期:2012-12-01 00:00:00
abstract::The fluorogenic sulfhydryl probe 7-diethylamino-3-(4'-maleimidylphenyl)-4-methylcoumarin (CPM) (1-50 nM) is used to characterize the functional role and location of highly reactive thiol groups on the ryanodine-sensitive Ca2+ release channel complex [i.e., ryanodine receptors (RyRs)] of skeletal and cardiac junctional...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-02-01 00:00:00
abstract::The cannabinoid analog abnormal cannabidiol [abn-cbd; (-)-4-(3-3,4-trans-p-menthadien-[1,8]-yl)-olivetol] does not bind to CB(1) or CB(2) receptors, yet it acts as a full agonist in relaxing rat isolated mesenteric artery segments. Vasorelaxation by abn-cbd is endothelium-dependent, pertussis toxin-sensitive, and is i...
journal_title:Molecular pharmacology
pub_type: 评论,杂志文章
doi:10.1124/mol.63.3.699
更新日期:2003-03-01 00:00:00
abstract::The chemotherapeutic anthracycline metabolite doxorubicinol (doxOL) has been shown to interact with and disrupt the function of the cardiac ryanodine receptor Ca2+ release channel (RyR2) in the sarcoplasmic reticulum (SR) membrane and the SR Ca2+ binding protein calsequestrin 2 (CSQ2). Normal increases in RyR2 activit...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.117.108183
更新日期:2017-11-01 00:00:00
abstract::The sulfoconjugation of tyrosyl residues is a widespread post-translational modification of biologically active proteins and peptides. The rat liver Golgi enzyme tyrosylprotein sulfotransferase has previously been shown to catalyze the transfer of a sulfate moiety from 5'-phosphoadenosine-3'-phosphosulfate to the synt...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1989-10-01 00:00:00
abstract::The gene encoding a human 5-hydroxytryptamine (5-HT)1 receptor subtype was isolated from a human placental genomic library by using oligonucleotide probes derived from transmembrane regions of the cloned human 5-HT1D beta receptor. The deduced amino acid sequence of the genomic clone hp75d is identical to that of the ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1992-08-01 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::The N-methyl-D-aspartate (NMDA) receptor is believed to play a major role in learning and in excitotoxic neuronal damage associated with stroke and epilepsy. Pregnenolone sulfate, a neurosteroid, specifically enhances NMDA-gated currents in spinal cord neurons, while inhibiting receptors for the inhibitory amino acids...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1991-09-01 00:00:00
abstract::Polyamides are a class of synthetic molecules that exhibit high-affinity, sequence-specific reversible binding in the DNA minor groove but are incapable of inducing DNA damage. In cell-free systems, polyamides have been shown to regulate gene expression by activation, repression, and antirepression. However, effective...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.104.006254
更新日期:2005-03-01 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