Novel anxiolytics that act as partial agonists at benzodiazepine receptors.

Abstract:

:Benzodiazepines in clinical use have a range of pharmacological activities. Some, e.g. sedation, tolerance and addiction, are not welcome. Undesirable side-effects of drugs are often controlled by developing compounds that bind more selectively to one particular receptor subtype. An alternative approach, discussed here by Willy Haefely and colleagues, is the development of partial agonists which exploit regional differences in receptor reserve to tease apart biological responses. Partial agonists for the benzodiazepine modulatory site on the GABAA complex have been developed and their pharmacological profiles can be interpreted to suggest that neurons mediating anticonvulsant and anti-anxiety effects do indeed have a higher receptor reserve than neurons mediating other unwanted effects. This suggests that benzodiazepine receptor partial agonists may have important therapeutic potential.

journal_name

Trends Pharmacol Sci

authors

Haefely W,Martin JR,Schoch P

doi

10.1016/0165-6147(90)90126-s

subject

Has Abstract

pub_date

1990-11-01 00:00:00

pages

452-6

issue

11

eissn

0165-6147

issn

1873-3735

pii

0165-6147(90)90126-S

journal_volume

11

pub_type

杂志文章,评审
  • Intracellular 5-HT 2C-receptor dephosphorylation: a new target for treating drug addiction.

    abstract::The 5-hydroxytryptamine (5-HT)(2C) receptor has received considerable attention as a target for treating drug addiction. 5-HT(2C)-receptor agonism, however, also induces side-effects. In this article, we review recent findings regarding the involvement of 5-HT(2C) receptors in behaviours related to drug addiction in a...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2006.07.003

    authors: Müller CP,Carey RJ

    更新日期:2006-09-01 00:00:00

  • Beyond vasodilatation: non-vasomotor roles of epoxyeicosatrienoic acids in the cardiovascular system.

    abstract::Epoxyeicosatrienoic acids (EETs), derived from arachidonic acid by cytochrome P450 epoxygenases, are potent vasodilators that function as endothelium-derived hyperpolarizing factors in some vascular beds. EETs are rapidly metabolized by soluble epoxide hydrolase to form dihydroxyeicosatrienoic acids (DHETs). Recent re...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2006.11.002

    authors: Larsen BT,Campbell WB,Gutterman DD

    更新日期:2007-01-01 00:00:00

  • Computational studies to predict or explain G protein coupled receptor polypharmacology.

    abstract::Since G protein-coupled receptors (GPCRs) belong to a very large superfamily of evolutionarily related receptors (>800 members in humans), and due to the rapid progress on their structural biology, they are ideal candidates for polypharmacology studies. Broad screening and bioinformatics/chemoinformatics have been app...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章

    doi:10.1016/j.tips.2014.10.009

    authors: Jacobson KA,Costanzi S,Paoletta S

    更新日期:2014-12-01 00:00:00

  • The developing use of heterozygous mutant mouse models in brain monoamine transporter research.

    abstract::5-Hydroxytryptamine (5-HT), dopamine and norepinephrine are important monoamine neurotransmitters implicated in multiple brain mechanisms and regulated by high-affinity transmembrane monoamine transporters. Although knockout mice lacking 5-HT, dopamine or norepinephrine transporters are widely used to assess brain mon...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2007.01.002

    authors: Kalueff AV,Ren-Patterson RF,Murphy DL

    更新日期:2007-03-01 00:00:00

  • Unveiling the role of network and systems biology in drug discovery.

    abstract::Network and systems biology offer a novel way of approaching drug discovery by developing models that consider the global physiological environment of protein targets, and the effects of modifying them, without losing the key molecular details. Here we review some recent advances in network and systems biology applied...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2009.11.006

    authors: Pujol A,Mosca R,Farrés J,Aloy P

    更新日期:2010-03-01 00:00:00

  • Does the ternary complex act as a secondary proton pump and a GTP synthase?

    abstract::It has been suggested that G protein-coupled receptors can act as proton transporters, with the activated G protein-coupled receptor transporting H+ across the membrane from the extracellular side to the cytoplasm. In this article, Paul Nederkoorn, Henk Timmerman and Gabriëlle Donné-Op den Kelder summarize the various...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/s0165-6147(00)89008-2

    authors: Nederkoorn PH,Timmerman H,Donné-Op den Kelder GM

    更新日期:1995-05-01 00:00:00

  • Sphingosine Kinase 2 in Autoimmune/Inflammatory Disease and the Development of Sphingosine Kinase 2 Inhibitors.

    abstract::The purpose of this Opinion is to present a case for targeting sphingosine kinase 2 (SK2) in autoimmune/inflammatory disease. Data obtained using Sphk2-/- mice suggest that SK2 is an anti-inflammatory enzyme, although this might be misleading because of a compensatory increase in the expression of a second isoform, sp...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2017.04.003

    authors: Pyne NJ,Adams DR,Pyne S

    更新日期:2017-07-01 00:00:00

  • Targeting PAR1: Now What?

    abstract::Protease-activated receptors (PARs) are a ubiquitously expressed class of G-protein-coupled receptors (GPCRs) that enable cells to respond to proteases in the extracellular environment in a nuanced and dynamic manner. PAR1 is the archetypal family member and has been the object of large-scale drug development programs...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2017.05.001

    authors: Flaumenhaft R,De Ceunynck K

    更新日期:2017-08-01 00:00:00

  • The elusive nature of intrinsic efficacy.

    abstract::In the discipline of pharmacology, drugs (ligands) are used as tools to elucidate the processes of biological systems. Because of this, pharmacologists strive to delineate all characteristics of drugs. Decades of research have resulted in the proposal that ligands possess two properties that are intrinsic to the ligan...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/s0165-6147(97)01138-3

    authors: Clarke WP,Bond RA

    更新日期:1998-07-01 00:00:00

  • GPR119 as a fat sensor.

    abstract::The GPR119 receptor is expressed predominantly in pancreatic β cells and in enteroendocrine cells. It is a major target for the development of anti-diabetic drugs that through GPR119 activation may stimulate both insulin and GLP-1 release. GPR119 can be activated by oleoylethanolamide and several other endogenous lipi...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2012.03.014

    authors: Hansen HS,Rosenkilde MM,Holst JJ,Schwartz TW

    更新日期:2012-07-01 00:00:00

  • Non-genomic loss of PTEN function in cancer: not in my genes.

    abstract::Loss of function of the phosphatase and tensin homolog (PTEN) tumour suppressor contributes to the development of many cancers. However, in contrast to classical models of tumour suppression, partial loss of PTEN function appears to be frequently observed in the clinic. In addition, studies of both humans and mice wit...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2010.12.005

    authors: Leslie NR,Foti M

    更新日期:2011-03-01 00:00:00

  • Regulation of transcription factor activity by interconnected post-translational modifications.

    abstract::Transcription factors comprise just over 7% of the human proteome and serve as gatekeepers of cellular function, integrating external signal information into gene expression programs that reconfigure cellular physiology at the most basic levels. Surface-initiated cell signaling pathways converge on transcription facto...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2013.11.005

    authors: Filtz TM,Vogel WK,Leid M

    更新日期:2014-02-01 00:00:00

  • Location, location, location...site-specific GPCR phosphorylation offers a mechanism for cell-type-specific signalling.

    abstract::It is now established that most of the approximately 800 G-protein-coupled receptors (GPCRs) are regulated by phosphorylation in a process that results in the recruitment of arrestins, leading to receptor desensitization and the activation of arrestin-dependent processes. This generalized view of GPCR regulation, howe...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2008.05.006

    authors: Tobin AB,Butcher AJ,Kong KC

    更新日期:2008-08-01 00:00:00

  • Techniques: fruit flies as models for neuropharmacological research.

    abstract::An unlikely animal model is gaining popularity in neuropharmacological research: the 2-mm fruit fly (Drosophila melanogaster). Drugs have been administered to adult flies in their food and, more recently, via gasses and injections. Pharmacological tools have introduced behavioral alterations in Drosophila reminiscent ...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/s0165-6147(02)00004-4

    authors: Manev H,Dimitrijevic N,Dzitoyeva S

    更新日期:2003-01-01 00:00:00

  • Endothelium-dependent hyperpolarization: a role in the control of vascular tone.

    abstract::Endothelial-dependent relaxation of vascular smooth muscle cells evoked by a number of agonists, including cholinomimetics and substance P, is often accompanied by an increase (repolarization and/or hyperpolarization) in the membrane potential. This change in membrane potential appears predominantly to reflect the act...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/s0165-6147(00)88969-5

    authors: Garland CJ,Plane F,Kemp BK,Cocks TM

    更新日期:1995-01-01 00:00:00

  • Rho kinase: a target for treating urinary bladder dysfunction?

    abstract::Urinary incontinence and other urinary storage symptoms are frequent in the general population but available treatments have limited efficacy and tolerability. Rho kinase (ROCK) has a central role in the regulation of smooth muscle contraction, including that of the urinary bladder. Recent experimental evidence indica...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2006.07.002

    authors: Peters SL,Schmidt M,Michel MC

    更新日期:2006-09-01 00:00:00

  • GPCRs in NLRP3 Inflammasome Activation, Regulation, and Therapeutics.

    abstract::The NLRP3 inflammasome is an intracellular multimeric protein complex which plays an important role in the pathogenesis of various human inflammatory diseases, such as diabetes, Alzheimer's disease and atherosclerosis. Recently, various G protein-coupled receptors (GPCRs) have been reported to be involved in the activ...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2018.07.002

    authors: Tang T,Gong T,Jiang W,Zhou R

    更新日期:2018-09-01 00:00:00

  • New genome-wide methods bring more power to yeast as a model organism.

    abstract::Recent developments in genetic research using Saccharomyces cerevisiae have provided rapid new methods for identifying the genes that control cellular responses to treatment with a wide variety of agents, including chemicals and radiation. This significantly increases the power of yeast as a model system for studying ...

    journal_title:Trends in pharmacological sciences

    pub_type: 新闻

    doi:10.1016/s0165-6147(02)02082-5

    authors: Game JC

    更新日期:2002-10-01 00:00:00

  • Folding Underlies Bidirectional Role of GPR37/Pael-R in Parkinson Disease.

    abstract::Since conformational flexibility, which is required for the function of a protein, comes at the expense of structural stability, many proteins, including G-protein-coupled receptors (GPCRs), are under constant risk of misfolding and aggregation. In this regard GPR37 (also named PAEL-R and ETBR-LP-1) takes a prominent ...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2017.05.006

    authors: Leinartaité L,Svenningsson P

    更新日期:2017-08-01 00:00:00

  • Behavioural pharmacology: 40+ years of progress, with a focus on glutamate receptors and cognition.

    abstract::Behavioural pharmacology is an interdisciplinary field at the intersection of several research areas that ultimately lead to the development of drugs for clinical use and build understanding of how brain functions enable cognition and behaviour. In this article, the development of behavioural pharmacology in the UK is...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2006.01.009

    authors: Robbins TW,Murphy ER

    更新日期:2006-03-01 00:00:00

  • A brief history of British Pharmacological Society meetings.

    abstract::The British Pharmacological Society (BPS) is currently celebrating its 75th anniversary. It is therefore a young society compared with some other biomedical societies and particularly when compared with the origins of the oldest learned societies. In this article, I briefly review the origins of learned societies and ...

    journal_title:Trends in pharmacological sciences

    pub_type: 历史文章,杂志文章

    doi:10.1016/j.tips.2006.01.001

    authors: Green AR

    更新日期:2006-03-01 00:00:00

  • Higher-order organization and regulation of adenylyl cyclases.

    abstract::There is increasing awareness of the compartmentalization of cAMP signalling--the means by which cAMP levels change in discrete domains of the cell with discrete local consequences. Current developments in understanding the organization of adenylyl cyclases in the plasma membrane are illuminating how the earliest part...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2006.06.002

    authors: Cooper DM,Crossthwaite AJ

    更新日期:2006-08-01 00:00:00

  • MDSC; the Most Important Cell You Have Never Heard Of.

    abstract::The myeloid-derived suppressor cell (MDSC) is the 'queen bee' of the tumor microenvironment. MDSCs protect the cancer from the patient's immune system, make the tumor resistant to immunotherapy, and allow the tumor to thrive while the patient withers away. Eliminating MDSCs should improve response rates to cancer ther...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2018.10.008

    authors: Tesi RJ

    更新日期:2019-01-01 00:00:00

  • Techniques: reporter mice - a new way to look at drug action.

    abstract::During the past decade remarkable progress in molecular genetics and the possibility of manipulating cells so that the expression of genes can directly 'report' on drug activity has produced major changes in drug development strategies. The recent description and pharmacological validation of reporter mice for in vivo...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2004.04.007

    authors: Maggi A,Ottobrini L,Biserni A,Lucignani G,Ciana P

    更新日期:2004-06-01 00:00:00

  • GABA and its receptors in the spinal cord.

    abstract::The importance of the inhibitory neurotransmitter, GABA, within higher centres of the mammalian brain is unquestionable. However, its role within the spinal cord is of equal significance. There have been numerous studies over the past two decades that have established GABA as a neurotransmitter at both post- and presy...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/s0165-6147(96)01013-9

    authors: Malcangio M,Bowery NG

    更新日期:1996-12-01 00:00:00

  • Eosinophil lysis and free granules: an in vivo paradigm for cell activation and drug development.

    abstract::Release of cytotoxic granule proteins from activated eosinophil granules is considered to be a key pathogenic mechanism in eosinophilic diseases. Degenerated eosinophils and extracellular eosinophil granules have been repeatedly depicted. The present overview describes evidence that eosinophil lysis and distribution o...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/s0165-6147(97)01042-0

    authors: Persson CG,Erjefält JS

    更新日期:1997-04-01 00:00:00

  • Functional, molecular and pharmacological advances in 5-HT7 receptor research.

    abstract::The 5-HT7 receptor was among a group of 5-HT receptors that were discovered using targeted cloning strategies 12 years ago. This receptor is a seven-transmembrane-domain G-protein-coupled receptor that is positively linked to adenylyl cyclase. The distributions of 5-HT7 receptor mRNA, immunolabeling and radioligand bi...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2004.07.002

    authors: Hedlund PB,Sutcliffe JG

    更新日期:2004-09-01 00:00:00

  • Small airways: an important but neglected target in the treatment of obstructive airway diseases.

    abstract::Changes in the structure and function of the small airways (<2mm diameter) are now recognized to play a major role in airflow limitation in both chronic obstructive pulmonary disease (COPD) and severe asthma. Increased thickness of the small airway wall causes lumenal narrowing, which can be further occluded by mucus ...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2008.04.003

    authors: Sturton G,Persson C,Barnes PJ

    更新日期:2008-07-01 00:00:00

  • Heterogeneity of the endothelial cell and its role in organ preference of tumour metastasis.

    abstract::The vascular endothelium is a remarkably heterogeneous organ. In addition to well-characterized anatomical diversity in situ, specific differences are increasingly being recognized between surface antigens on endothelial cells from different tissues, including absence of the classic endothelial marker factor VIII-rela...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/0165-6147(91)90637-8

    authors: McCarthy SA,Kuzu I,Gatter KC,Bicknell R

    更新日期:1991-12-01 00:00:00

  • Targeting GLI factors to inhibit the Hedgehog pathway.

    abstract::Hedgehog (Hh) signaling has emerged in recent years as an attractive target for anticancer therapy because its aberrant activation is implicated in several cancers. Major progress has been made in the development of SMOOTHENED (SMO) antagonists, although they have shown several limitations due to downstream SMO pathwa...

    journal_title:Trends in pharmacological sciences

    pub_type: 杂志文章,评审

    doi:10.1016/j.tips.2015.05.006

    authors: Infante P,Alfonsi R,Botta B,Mori M,Di Marcotullio L

    更新日期:2015-08-01 00:00:00