Search results for: John R. Atack

Items from 1 to 20 out of 51 results

article

Relating neurosteroid modulation of inhibitory neurotransmission to behaviour

Delia Belelli, Grant D. Phillips, John R. Atack, Jeremy J. Lambert

Journal of Neuroendocrinology > 34 > 2 > n/a - n/a

Studies in the 1980s revealed endogenous metabolites of progesterone and deoxycorticosterone to be potent, efficacious, positive allosteric modulators (PAMs) of the GABA_A receptor (GABA_AR). The discovery that such steroids are locally synthesised in the central nervous system (CNS) promoted the thesis that neural inhibition in the CNS may be “fine‐tuned” by these neurosteroids to influence behaviour...

article

Lipophilic nalmefene prodrugs to achieve a one-month sustained release

Tim Gaekens, Michel Guillaume, Herman Borghys, Loeckie L. De Zwart, more

Journal of Controlled Release > 2016 > 232 > C > 196-202

Nalmefene is an opioid antagonist which as a once-a-day tablet formulation has recently been approved for reducing ethanol intake in alcoholic subjects. In order to address the compliance issue in this patient population, a number of potential nalmefene prodrugs were synthesized with the aim of providing a formulation that could provide plasma drug concentrations in the region of 0.5–1.0ng/mL for...

chapter

Development of Subtype-Selective GABA_A Receptor Compounds for the Treatment of Anxiety, Sleep Disorders and Epilepsy

John R. Atack

GABA and Sleep > Basic Physiology and Pharmacology > 25-72

There is little doubt regarding the therapeutic possibilities of modulation of GABA_A receptor function as exemplified by the clinical utility of benzodiazepines for half a century. The emerging understanding of the role of different GABA_A receptor subtypes in mediating different physiological functions and pathological processes continues to offer opportunities for novel therapeutics. However, the...

chapter

GABA_A Receptor α2/α3 Subtype-Selective Modulators as Potential Nonsedating Anxiolytics

John R. Atack

Current Topics in Behavioral Neurosciences > Behavioral Neurobiology of Anxiety and Its Treatment > 331-360

Nonselective benzodiazepines exert their pharmacological effects via GABA_A receptors containing either an α1, α2, α3, or α5 subunit. The use of subtype-selective tool compounds along with transgenic mice has formed the conceptual framework for defining the requirements of subtype-selective compounds with potentially novel pharmacological profiles. More specifically, compounds which allosterically...

article

The discovery and synthesis of JNJ 31020028, a small molecule antagonist of the Neuropeptide Y Y2 receptor

Devin M. Swanson, Victoria D. Wong, Jill A. Jablonowski, Chandra Shah, more

Bioorganic & Medicinal Chemistry Letters > 2011 > 21 > 18 > 5552-5556

A series of small molecules based on a chemotype identified from our compound collection were synthesized and tested for binding affinity (IC ₅₀ ) at the human Neuropeptide Y Y ₂ receptor (NPY Y ₂ ). Six of the 23 analogs tested possessed an NPY Y ₂ IC ₅₀ ⩽15nM. One member of this series, JNJ 31020028, is a selective, high affinity, receptor antagonist existing...

article

Contribution of GABA_A receptors containing α3 subunits to the therapeutic-related and side effects of benzodiazepine-type drugs in monkeys

Bradford D. Fischer, John R. Atack, Donna M. Platt, David S. Reynolds, more

Psychopharmacology > 2011 > 215 > 2 > 311-319

Rationale Experimental evidence suggests that the differential behavioral effects of benzodiazepines depend on their relative actions at γ-aminobutyric acid type A (GABA_A) receptors that contain either an α1, α2, α3, or α5 subunit. Objectives The present study was aimed at understanding the role of α3 subunit-containing GABA_A (α3GABA_A) receptors by examining the behavioral pharmacology of TP003...

article

Pre-clinical characterization of aryloxypyridine amides as histamine H3 receptor antagonists: Identification of candidates for clinical development

Michael A. Letavic, Leah Aluisio, John R. Atack, Pascal Bonaventure, more

Bioorganic & Medicinal Chemistry Letters > 2010 > 20 > 14 > 4210-4214

The pre-clinical characterization of novel aryloxypyridine amides that are histamine H ₃ receptor antagonists is described. These compounds are high affinity histamine H ₃ ligands that penetrate the CNS and occupy the histamine H ₃ receptor in rat brain. Several compounds were extensively profiled pre-clinically leading to the identification of two compounds suitable for nomination...

article

Novel substituted pyrrolidines are high affinity histamine H3 receptor antagonists

Emily M. Stocking, Leah Aluisio, John R. Atack, Pascal Bonaventure, more

Bioorganic & Medicinal Chemistry Letters > 2010 > 20 > 9 > 2755-2760

Pre-clinical characterization of novel substituted pyrrolidines that are high affinity histamine H ₃ receptor antagonists is described. These compounds efficiently penetrate the CNS and occupy the histamine H ₃ receptor in rat brain following oral administration. One compound, (2S,4R)-1-[2-(4-cyclobutyl-[1,4]diazepane-1-carbonyl)-4-(3-fluoro-phenoxy)-pyrrolidin-1-yl]-ethanone, was...

article

Discriminative stimulus effects of L-838,417 (7-tert-butyl-3-(2,5-difluoro-phenyl)-6-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-[1,2,4]triazolo[4,3-b]pyridazine): Role of GABAA receptor subtypes

Stephanie C. Licata, Donna M. Platt, Daniela Rüedi-Bettschen, John R. Atack, more

Neuropharmacology > 2010 > 58 > 2 > 357-364

Previous reports suggest that γ-aminobutyric acid type A (GABA _A ) receptors containing α1 subunits may play a pivotal role in mediating the discriminative stimulus effects of benzodiazepines (BZs). L-838,417 (7-tert-Butyl-3-(2,5-difluoro-phenyl)-6-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-[1,2,4]triazolo[4,3-b]pyridazine) is a GABA _A receptor modulator with intrinsic efficacy in vitro...

article

Preclinical and clinical pharmacology of the GABAA receptor α5 subtype-selective inverse agonist α5IA

John R. Atack

Pharmacology and Therapeutics > 2010 > 125 > 1 > 11-26

α5IA is a triazolophthalazine that selectively attenuates the effects of GABA at GABA _A receptors containing an α5 subunit. It enhances long-term potentiation in an in vitro model of mouse hippocampal synaptic plasticity, gives good in vivo receptor occupancy and improves cognitive performance in normal rats as measured using the delayed-matching-to-place version of the Morris water maze yet,...

article

In vitro and in vivo characterization of JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), a selective brain penetrant small molecule antagonist of the neuropeptide Y Y₂ receptor

James R. Shoblock, Natalie Welty, Diane Nepomuceno, Brian Lord, more

Psychopharmacology > 2010 > 208 > 2 > 265-277

Rationale The lack of potent, selective, brain penetrant Y₂ receptor antagonists has hampered in vivo functional studies of this receptor. Objective Here, we report the in vitro and in vivo characterization of JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), a novel Y₂ receptor antagonist. Methods The affinity of JNJ-31020028...

article

The complexity of the GABAA receptor shapes unique pharmacological profiles

Charlotte D’Hulst, John R. Atack, R. Frank Kooy

Drug Discovery Today > 2009 > 14 > 17-18 > 866-875

Gamma-amino butyric acid (GABA) is the most abundant inhibitory neurotransmitter in the central nervous system (CNS) and many physiological actions are modulated by GABA _A receptors. These chloride channels can be opened by GABA and are a target for a variety of important drugs such as benzodiazepines, barbiturates, neuroactive steroids, convulsants and anaesthetics. GABA _A receptors...

article

In Vivo Characterization and Dynamic Receptor Occupancy Imaging of TPA023B, an α2/α3/α5 Subtype Selective γ-Aminobutyric Acid–A Partial Agonist

Koen Van Laere, Guy Bormans, Sandra M. Sanabria-Bohórquez, Tjibbe de Groot, more

Biological Psychiatry > 2008 > 64 > 2 > 153-161

A novel, high-affinity (.7–2.0 nmol) compound that selectively activates the α2, α3, and α5 (but not α1) γ-aminobutyric acid–A (GABA _A ) receptor subtypes, TPA023B (2′,6-difluoro-5′-[3-(1-hydroxy-1-methylethyl) imidazo[1,2-b][1,2,4]triazin-7-yl][1,1′-biphenyl]-2-carbonitrile) was pharmacologically characterized and studied by means of positron emission tomography (PET) to determine dynamic...

article

L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for α5-containing GABAA receptors

John R. Atack, Peter J. Bayley, Guy R. Seabrook, Keith A. Wafford, more

Neuropharmacology > 2006 > 51 > 6 > 1023-1029

The in vitro and in vivo properties of L-655,708, a compound with higher affinity for GABA _A receptors containing an α5 compared to an α1, α2 or α3 subunit have been examined further. This compound has weak partial inverse agonist efficacy at each of the four subtypes but, and consistent with the binding data, has higher functional affinity for the α5 subtype. In a mouse hippocampal slice...

article

A comparative assessment of γ-secretase activity in transgenic and non-transgenic rodent brain

Julian L. Goggi, Huw D. Lewis, Joanie Mok, Tim Harrison, more

Journal of Neuroscience Methods > 2006 > 157 > 2 > 246-252

Amyloid-beta (Aβ) deposits are one of the hallmarks of the neuropathological degeneration observed in Alzheimer's disease (AD) and Aβ concentrations have been reported to vary in different brain regions of AD patients. Aβ is produced by the sequential cleavage of amyloid precursor protein (APP) by β-secretase and γ-secretase, respectively. Previous studies have shown that over-expression of the γ-secretase...

article

The proconvulsant effects of the GABAA α5 subtype-selective compound RY-080 may not be α5-mediated

John R. Atack, Peter J. Bayley, Stephen R. Fletcher, Ruth M. McKernan, more

European Journal of Pharmacology > 2006 > 548 > 1-3 > 77-82

RY-080 (ethyl 8-ethynyl-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylate) is an imidazobenzodiazepine with 40–50-fold higher affinity for the benzodiazepine binding site of α5- rather than α1-, α2- or α3-containing GABA _A receptors. Previous data describing RY-080 as being convulsant suggests that inverse agonists selective for the α5 subtype may not be suitable...

article

Comparison of in vivo and ex vivo [3H]flumazenil binding assays to determine occupancy at the benzodiazepine binding site of rat brain GABAA receptors

Jennifer Li, Rebecca L. Fish, Susan M. Cook, Frederick D. Tattersall, more

Neuropharmacology > 2006 > 51 > 1 > 168-172

In the present study, the occupancy of flumazenil (Ro 15-1788; 1–30mg/kg p.o.) at the benzodiazepine site of rat brain GABA _A receptors was compared using in vivo and ex vivo binding methodologies with [ ³ H]flumazenil as the radioligand. Animals either received tracer quantities of [ ³ H]flumazenil 3min before being killed for the in vivo binding, or were killed and brain...

article

2,3,7-Trisubstituted pyrazolo[1,5-d][1,2,4]triazines: Functionally selective GABAA α3-subtype agonists

Robert W. Carling, Michael G.N. Russell, Kevin W. Moore, Andrew Mitchinson, more

Bioorganic & Medicinal Chemistry Letters > 2006 > 16 > 13 > 3550-3554

Novel synthetic routes have been devised for the preparation of previously inaccessible 2,3,7-trisubstituted pyrazolo[1,5-d][1,2,4]triazines 2. These compounds are high affinity ligands for the GABA _A benzodiazepine binding site and some analogues show functional selectivity for agonism at α3-containing receptors over α1-containing receptors with the lead compound being 32.

article

The in vivo properties of pagoclone in rat are most likely mediated by 5′-hydroxy pagoclone

John R. Atack, Andy Pike, George Marshall, Jo Stanley, more

Neuropharmacology > 2006 > 50 > 6 > 677-689

The cyclopyrrolone pagoclone binds with roughly equivalent high affinity (0.7–9.1nM) to the benzodiazepine binding site of human recombinant GABA _A receptors containing either an α1, α2, α3 or α5 subunit. However, whereas it was a partial agonist at α1-, α2- and α5-containing GABA _A receptors, pagoclone was a full agonist at receptors containing an α3 subunit. In the rat elevated plus...

article

A Pyridazine Series of α2/α3 Subtype Selective GABA _A Agonists for the Treatment of Anxiety

Richard T. Lewis, Wesley P. Blackaby, Timothy Blackburn, Andrew S. R. Jennings, more

Journal of Medicinal Chemistry > 2006 > 49 > 8 > 2600 - 2610

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Search results for: John R. Atack

Relating neurosteroid modulation of inhibitory neurotransmission to behaviour

Lipophilic nalmefene prodrugs to achieve a one-month sustained release

Development of Subtype-Selective GABA_A Receptor Compounds for the Treatment of Anxiety, Sleep Disorders and Epilepsy

GABA_A Receptor α2/α3 Subtype-Selective Modulators as Potential Nonsedating Anxiolytics

The discovery and synthesis of JNJ 31020028, a small molecule antagonist of the Neuropeptide Y Y2 receptor

Contribution of GABA_A receptors containing α3 subunits to the therapeutic-related and side effects of benzodiazepine-type drugs in monkeys

Pre-clinical characterization of aryloxypyridine amides as histamine H3 receptor antagonists: Identification of candidates for clinical development

Novel substituted pyrrolidines are high affinity histamine H3 receptor antagonists

Discriminative stimulus effects of L-838,417 (7-tert-butyl-3-(2,5-difluoro-phenyl)-6-(2-methyl-2H-[1,2,4]triazol-3-ylmethoxy)-[1,2,4]triazolo[4,3-b]pyridazine): Role of GABAA receptor subtypes

Preclinical and clinical pharmacology of the GABAA receptor α5 subtype-selective inverse agonist α5IA

In vitro and in vivo characterization of JNJ-31020028 (N-(4-{4-[2-(diethylamino)-2-oxo-1-phenylethyl]piperazin-1-yl}-3-fluorophenyl)-2-pyridin-3-ylbenzamide), a selective brain penetrant small molecule antagonist of the neuropeptide Y Y₂ receptor

The complexity of the GABAA receptor shapes unique pharmacological profiles

In Vivo Characterization and Dynamic Receptor Occupancy Imaging of TPA023B, an α2/α3/α5 Subtype Selective γ-Aminobutyric Acid–A Partial Agonist

L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for α5-containing GABAA receptors

A comparative assessment of γ-secretase activity in transgenic and non-transgenic rodent brain

The proconvulsant effects of the GABAA α5 subtype-selective compound RY-080 may not be α5-mediated

Comparison of in vivo and ex vivo [3H]flumazenil binding assays to determine occupancy at the benzodiazepine binding site of rat brain GABAA receptors

2,3,7-Trisubstituted pyrazolo[1,5-d][1,2,4]triazines: Functionally selective GABAA α3-subtype agonists

The in vivo properties of pagoclone in rat are most likely mediated by 5′-hydroxy pagoclone

A Pyridazine Series of α2/α3 Subtype Selective GABA _A Agonists for the Treatment of Anxiety

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