Abstract:
:Recent clinical studies reveal that selective agonists of group II metabotropic glutamate (mGlu) receptors have robust efficacy in treating positive and negative symptoms in patients with schizophrenia. Group II mGlu receptor agonists also modulate the in vivo activity of psychotomimetic drugs and reduce the ability of psychotomimetic hallucinogens to increase glutamatergic transmission. Because increased excitation of the medial prefrontal cortex (mPFC) has been implicated in pathophysiology of schizophrenia, the ability of group II mGlu receptor agonists to reduce hallucinogenic drug action in this region is believed to be directly related to their antipsychotic efficacy. A novel class of ligands, termed positive allosteric modulators, has recently been identified, displaying exceptional mGlu2 receptor selectivity. These compounds do not activate mGlu2 receptors directly but potentiate the ability of glutamate and other agonists to activate this receptor. We now report that the mGlu2 receptor-selective positive allosteric modulator biphenyl-indanone A (BINA) modulates excitatory neurotransmission in the mPFC and attenuates the in vivo actions of the hallucinogenic 5-HT(2A/2C) receptor agonist (-)2,5-dimethoxy-4-bromoamphetamine [(-)DOB]. BINA attenuates serotonin-induced increases in spontaneous excitatory postsynaptic currents in the mPFC, mimicking the effect of the mGlu2/3 receptor agonist (2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine (DCG-IV). In addition, BINA reduced (-)DOB-induced head twitch behavior and Fos expression in mPFC, effects reversed by pretreatment with the mGlu2/3 receptor antagonist 2S-2-amino-2-(1S,2S-2-carboxycyclopropan-1-yl) -3 - (xanth-9-yl-)propionic acid (LY341495). These data confirm the relevance of excitatory signaling in the mPFC to the behavioral actions of hallucinogens and further support the targeting of mGlu2 receptors as a novel strategy for treating glutamatergic dysfunction in schizophrenia.
journal_name
Mol Pharmacoljournal_title
Molecular pharmacologyauthors
Benneyworth MA,Xiang Z,Smith RL,Garcia EE,Conn PJ,Sanders-Bush Edoi
10.1124/mol.107.035170subject
Has Abstractpub_date
2007-08-01 00:00:00pages
477-84issue
2eissn
0026-895Xissn
1521-0111pii
mol.107.035170journal_volume
72pub_type
杂志文章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::Anaplastic thyroid carcinoma (ATC) is among the most aggressive malignancies known and is characterized with rapid growth, early invasion, and complete refractoriness to current therapies. Here we report that triptolide, a small molecule from a Chinese herb, could potently inhibit proliferation in vitro, angiogenesis ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.108.052605
更新日期:2009-04-01 00:00:00
abstract::The observations from Dunlap and Fischbach that transmitter-mediated shortening of the duration of action potentials could be caused by a decrease in calcium conductance led to numerous studies of the mechanisms of modulation of voltage-dependent calcium channels. Calcium channels are well known targets for inhibition...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.104.002261
更新日期:2004-11-01 00:00:00
abstract::The rat mu-opioid receptor clone in which novel exon 5 was found in the place of exon 4 (MOR-1B) was one of the first MOR-1 variants described. We now have identified the mouse homolog of the rat MOR-1B as well as four additional variants derived from splicing from exon 3 into different sites within exon 5. The sequen...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.105.011858
更新日期:2005-09-01 00:00:00
abstract::Voltage-gated sodium channels (Navs) are promising targets for analgesic and antiepileptic therapies. Although specificity between Nav subtypes may be desirable to target specific neural types, such as nociceptors in pain, many broadly acting Nav inhibitors are clinically beneficial in neuropathic pain and epilepsy. H...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/molpharm.120.000079
更新日期:2021-01-01 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::Activation of endothelial nitric-oxide synthase (eNOS) has been shown to occur through various pathways involving increases in the cytosolic Ca(2+) concentration, activation of the phosphatidylinositol-3' kinase/Akt pathway, as well as regulation by other kinases and by protein-protein interactions. We have recently r...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.63.4.886
更新日期:2003-04-01 00:00:00
abstract::The firmest candidate among the transmembrane portions of the nicotinic acetylcholine receptor (AChR) to be in contact with the lipid bilayer is the fourth segment, M4. To explore the contribution of alphaM4 amino acid residues of mouse AChR to channel gating, we combined site-directed mutagenesis with single-channel ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.54.1.146
更新日期:1998-07-01 00:00:00
abstract::Comparative molecular field analysis (CoMFA) predicts that the large electrostatic field around the phosphate groups of ATP plays a crucial role in stabilizing the open state of the cardiac ryanodine receptor (RyR) channel. We therefore investigated the effects of adenosine-5'-(beta,gamma-methylenetriphosphate) (AMP-P...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.63.1.174
更新日期:2003-01-01 00:00:00
abstract::The effects of the insulin-releasing sulfonylurea tolbutamide on the cytoplasmic Ca2+ concentration [( Ca2+]i) in individual pancreatic beta-cells or suspensions of beta-cells were analyzed using the probe fura-2 and dual-wavelength fluorometry. Subsequent additions of 1, 10, and 100 microM tolbutamide induced a grade...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1990-03-01 00:00:00
abstract::Molecular chaperone heat shock protein 90 (HSP90) is involved in oncogenic signaling pathways including epithelial-mesenchymal transition (EMT), a key process in tumor initiation, progression, metastasis, and chemoresistance. The molecular mechanisms underlying the involvement of HSP90 in EMT are still under investiga...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.119.116137
更新日期:2019-08-01 00:00:00
abstract::The instability of the solubilized/purified form, the lack of catalytic activity of the stabilized, macrolide-complexed form, and the compromised catalytic activity of the decomplexed form of steroid-inducible cytochrome P450IIIA1 motivated further investigations of the substrate specificity of this isozyme. A major c...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1988-11-01 00:00:00
abstract::(+/-)-6' beta-Fluoroaristeromycin (F-C-Ado) is a potent and competitive inhibitor of purified S-adenosylhomocysteine (AdoHcy) hydrolase isolated from murine L929 cells (Ki = 3.1 nM). It also inhibits vaccinia virus and vesicular stomatitis virus replication in L929 cells, at a 90% inhibitory dose (ID90) of 3.5 and 13 ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1991-06-01 00:00:00
abstract::Carbachol is 100 times more potent for inhibiting cyclic AMP formation than for stimulating phosphoinositide (PI) hydrolysis in chick heart cells. To determine whether this reflects differences in agonist affinity of the receptor(s) coupled to the two responses, we measured these functional responses following removal...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1986-12-01 00:00:00
abstract::We examined the influence of the molecular structure of four novel adamantane derivatives on their ability to block the channels of nicotinic acetylcholine (ACh) and N-methyl-D-aspartate (NMDA) receptors. The structure of the drugs is Ad-CH2-N+H2-(CH2)5-R, where Ad is adamantane and R was varied from ammonium (IEM-175...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1995-03-01 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::Thiourea, phenylthiourea, and methimazole perfused into rat liver stimulated the biliary efflux of GSSG without affecting the excretion of GSH into either the bile or the caval perfusate. The thiocarbamide moiety appears essential, since perfusion with urea, phenylurea, or N-methylimidazole did not stimulate GSSG rele...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1984-07-01 00:00:00
abstract::Activation of alpha 1-adrenergic receptors (alpha 1-AR) increases Na+/H+ exchange (NHE) in proximal tubule. NHE mediates the majority of active Na+ absorption in the proximal tubule. Three alpha 1-AR subtypes have been detected in kidney by molecular and binding techniques. We detected message for all three alpha 1-AR...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.52.6.1010
更新日期:1997-12-01 00:00:00
abstract::We showed previously that microtubule disassembly by vinblastine induces the proto-oncogene c-myc in epithelial mammary HBL100 cells. In this study, we demonstrate that vinblastine treatment in these cells, in contrast to what was observed with the colon adenocarcinoma cell line HT29-D4, activated the transcription fa...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.59.5.1165
更新日期:2001-05-01 00:00:00
abstract::Cytokines are thought to cause the depression of cytochrome P-450 (CYP)-associated drug metabolism in humans during inflammation and infection. We have examined the role of five cytokines, i.e., interleukin-1 beta, interleukin-4, interleukin-6, tumor necrosis factor-alpha, and interferon-gamma, on the expression of CY...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-10-01 00:00:00
abstract::The nucleoside analog 5-azacytidine is an archetypical drug for epigenetic cancer therapy, and its clinical effectiveness has been demonstrated in the treatment of myelodysplastic syndromes (MDS) and acute myelogenous leukemia (AML). However, therapy resistance in patients with MDS/AML remains a challenging issue. Mem...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.113.086801
更新日期:2013-09-01 00:00:00
abstract::Seven transmembrane G protein-coupled receptors (GPCRs) are often phosphorylated at the C terminus and on intracellular loops in response to various extracellular stimuli. Phosphorylation of GPCRs by GPCR kinases and certain other kinases can promote the recruitment of arrestin molecules. The arrestins critically regu...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.116.107839
更新日期:2017-09-01 00:00:00
abstract::G protein-coupled receptor (GPCR) kinases (GRKs) play a key role in terminating signals initiated by agonist-bound GPCRs. However, chronic stimulation of GPCRs, such as that which occurs during heart failure, leads to the overexpression of GRKs and maladaptive downregulation of GPCRs on the cell surface. We previously...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.119.118661
更新日期:2020-06-01 00:00:00
abstract::In this study, the expression of CYP26 is examined in relation to retinoid-induced mucosecretory differentiation in human tracheobronchial epithelial (HTBE) cells and compared with that in human lung carcinoma cell lines. In HTBE cells, retinoic acid (RA) inhibits squamous differentiation and induces mucous cell diffe...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.58.3.483
更新日期:2000-09-01 00:00:00
abstract::Reuptake of glutamate in astrocytes, a critical mechanism involved in the maintenance of physiological excitatory amino acid neurotransmission, is inhibited by both arachidonic acid (AA) and reactive oxygen species (ROS), via incompletely defined molecular mechanisms. Because ROS are generated during AA metabolism and...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1994-11-01 00:00:00
abstract::The precise mechanism by which the broad-spectrum anti-RNA virus agent ribavirin elicits its in vitro antiviral effect has remained a matter of debate. We have demonstrated that inhibition of cellular inosine monophosphate dehydrogenase (IMPDH) activity, and thus depletion of intracellular GTP pools, is the predominan...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:10.1124/mol.105.020057
更新日期:2006-04-01 00:00:00
abstract::Rat cerebellar granule cells express 5-hydroxytryptamine (5-HT)2 receptors that mediate phosphoinositide turnover by a pertussis toxin-sensitive mechanism. Prestimulation of these neurons with 10 microM 5-HT or (+/-)-2,5-dimethoxy-4-iodophenyl-2-aminopropane [(+/-)-DOI], a putative 5-HT2 receptor agonist, resulted in ...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1993-03-01 00:00:00
abstract::The benzomorphan opiate, (-)N-allynormetazocine [(-)ANMC, (-)SKF10047], has been shown previously to bind two distinct sites on acetylcholine receptor (AChR)-rich membranes from Torpedo electroplaque. The low affinity site seems to correspond to the site for noncompetitive blockers on the AChR. The high affinity site,...
journal_title:Molecular pharmacology
pub_type: 杂志文章
doi:
更新日期:1987-10-01 00:00:00
abstract::Activators of G protein signaling (AGS), initially discovered in the search for receptor-independent activators of G protein signaling, define a broad panel of biologic regulators that influence signal transfer from receptor to G-protein, guanine nucleotide binding and hydrolysis, G protein subunit interactions, and/o...
journal_title:Molecular pharmacology
pub_type: 杂志文章,评审
doi:10.1124/mol.113.090068
更新日期:2014-03-01 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