John R Atack

Summary

Affiliation: Johnson and Johnson Pharmaceutical Research and Development
Country: USA

Publications

  1. doi request reprint GABA(A) receptor subtype-selective efficacy: TPA023, an alpha2/alpha3 selective non-sedating anxiolytic and alpha5IA, an alpha5 selective cognition enhancer
    John R Atack
    Neuroscience, Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium
    CNS Neurosci Ther 14:25-35. 2008
  2. ncbi request reprint GABAA receptor subtype-selective modulators. I. α2/α3-selective agonists as non-sedating anxiolytics
    John R Atack
    Department of Neuroscience, Janssen Pharmaceutical Research and Development, Beerse, Belgium
    Curr Top Med Chem 11:1176-202. 2011
  3. ncbi request reprint GABAA receptor subtype-selective modulators. II. α5-selective inverse agonists for cognition enhancement
    John R Atack
    Department of Neuroscience, Janssen Pharmaceutical Research and Development, Beerse, Belgium
    Curr Top Med Chem 11:1203-14. 2011
  4. ncbi request reprint GABAA receptor alpha2/alpha3 subtype-selective modulators as potential nonsedating anxiolytics
    John R Atack
    Department of Neuroscience, Johnson and Johnson Pharmaceutical Research and Development, Building 020, Room 1A6, Turnhoutseweg 30, B 2340, Beerse, Belgium
    Curr Top Behav Neurosci 2:331-60. 2010
  5. doi request reprint Subtype-selective GABA(A) receptor modulation yields a novel pharmacological profile: the design and development of TPA023
    John R Atack
    Department of Neuroscience, Johnson and Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, Beerse B 2340, Belgium
    Adv Pharmacol 57:137-85. 2009
  6. ncbi request reprint Imidazo[1,2-a]pyrazin-8-ones, imidazo[1,2-d][1,2,4]triazin-8-ones and imidazo[2,1-f][1,2,4]triazin-8-ones as alpha2/alpha3 subtype selective GABA A agonists for the treatment of anxiety
    Simon C Goodacre
    Neuroscience Research Centre, Merck, Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Bioorg Med Chem Lett 16:1582-5. 2006
  7. ncbi request reprint Discovery of functionally selective 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazines as GABA A receptor agonists at the alpha3 subunit
    Michael G N Russell
    Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U K
    J Med Chem 48:1367-83. 2005
  8. ncbi request reprint L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for alpha5-containing GABAA receptors
    John R Atack
    Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Neuropharmacology 51:1023-9. 2006
  9. ncbi request reprint Evidence for a significant role of alpha 3-containing GABAA receptors in mediating the anxiolytic effects of benzodiazepines
    Rebecca Dias
    The Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Harlow, Essex CM20 2QR, United Kingdom
    J Neurosci 25:10682-8. 2005
  10. ncbi request reprint 7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine: a functionally selective gamma-aminobutyric acid(A) (GABA(A)) alpha2/alpha3-subtype selective agonist that exhibits potent anxiolytic activi
    Robert W Carling
    Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    J Med Chem 48:7089-92. 2005

Collaborators

Detail Information

Publications52

  1. doi request reprint GABA(A) receptor subtype-selective efficacy: TPA023, an alpha2/alpha3 selective non-sedating anxiolytic and alpha5IA, an alpha5 selective cognition enhancer
    John R Atack
    Neuroscience, Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium
    CNS Neurosci Ther 14:25-35. 2008
    ....
  2. ncbi request reprint GABAA receptor subtype-selective modulators. I. α2/α3-selective agonists as non-sedating anxiolytics
    John R Atack
    Department of Neuroscience, Janssen Pharmaceutical Research and Development, Beerse, Belgium
    Curr Top Med Chem 11:1176-202. 2011
    ....
  3. ncbi request reprint GABAA receptor subtype-selective modulators. II. α5-selective inverse agonists for cognition enhancement
    John R Atack
    Department of Neuroscience, Janssen Pharmaceutical Research and Development, Beerse, Belgium
    Curr Top Med Chem 11:1203-14. 2011
    ..Overall, these studies demonstrate the feasibility of adopting a selective efficacy approach in the identification of α5 selective GABA(A) receptor inverse agonists...
  4. ncbi request reprint GABAA receptor alpha2/alpha3 subtype-selective modulators as potential nonsedating anxiolytics
    John R Atack
    Department of Neuroscience, Johnson and Johnson Pharmaceutical Research and Development, Building 020, Room 1A6, Turnhoutseweg 30, B 2340, Beerse, Belgium
    Curr Top Behav Neurosci 2:331-60. 2010
    ....
  5. doi request reprint Subtype-selective GABA(A) receptor modulation yields a novel pharmacological profile: the design and development of TPA023
    John R Atack
    Department of Neuroscience, Johnson and Johnson Pharmaceutical Research and Development, Turnhoutseweg 30, Beerse B 2340, Belgium
    Adv Pharmacol 57:137-85. 2009
    ..Collectively, these data demonstrate that the alpha2/alpha3-selective partial agonist efficacy of TPA023 translates into a novel pharmacological profile...
  6. ncbi request reprint Imidazo[1,2-a]pyrazin-8-ones, imidazo[1,2-d][1,2,4]triazin-8-ones and imidazo[2,1-f][1,2,4]triazin-8-ones as alpha2/alpha3 subtype selective GABA A agonists for the treatment of anxiety
    Simon C Goodacre
    Neuroscience Research Centre, Merck, Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Bioorg Med Chem Lett 16:1582-5. 2006
    ....
  7. ncbi request reprint Discovery of functionally selective 7,8,9,10-tetrahydro-7,10-ethano-1,2,4-triazolo[3,4-a]phthalazines as GABA A receptor agonists at the alpha3 subunit
    Michael G N Russell
    Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, U K
    J Med Chem 48:1367-83. 2005
    ..This was the first indication that selectivity in efficacy in the required direction could be achieved in this series...
  8. ncbi request reprint L-655,708 enhances cognition in rats but is not proconvulsant at a dose selective for alpha5-containing GABAA receptors
    John R Atack
    Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Neuropharmacology 51:1023-9. 2006
    ..These data further support the potential of alpha5-containing GABA(A) receptors as a target for novel cognition enhancing drugs...
  9. ncbi request reprint Evidence for a significant role of alpha 3-containing GABAA receptors in mediating the anxiolytic effects of benzodiazepines
    Rebecca Dias
    The Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Harlow, Essex CM20 2QR, United Kingdom
    J Neurosci 25:10682-8. 2005
    ..Together, these data show that potentiation of alpha3-containing GABA(A) receptors is sufficient to produce the anxiolytic effects of BZs and that alpha2 potentiation may not be necessary...
  10. ncbi request reprint 7-(1,1-Dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine: a functionally selective gamma-aminobutyric acid(A) (GABA(A)) alpha2/alpha3-subtype selective agonist that exhibits potent anxiolytic activi
    Robert W Carling
    Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    J Med Chem 48:7089-92. 2005
    ..Herein we describe a novel series of GABA(A) alpha2/alpha3 subtype-selective agonists leading to the identification of the development candidate 17, a nonsedating anxiolytic in preclinical animal assays...
  11. ncbi request reprint Role of GABAA alpha5-containing receptors in ethanol reward: the effects of targeted gene deletion, and a selective inverse agonist
    David N Stephens
    Department of Psychology, School of Life Sciences, University of Sussex, Brighton, BN1 9QG, UK
    Eur J Pharmacol 526:240-50. 2005
    ..Although inverse agonists acting at alpha5-containing receptors reduce ethanol self-administration, alpha5 subunits may not be essential to signaling ethanol reward...
  12. ncbi request reprint Imidazo[1,2-b][1,2,4]triazines as alpha2/alpha3 subtype selective GABA A agonists for the treatment of anxiety
    Andrew S R Jennings
    Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Bioorg Med Chem Lett 16:1477-80. 2006
    ..SAR studies to optimise this functional selectivity, pharmacokinetic and behavioural data are described...
  13. ncbi request reprint Imidazo[1,2-a]pyrimidines as functionally selective and orally bioavailable GABA(A)alpha2/alpha3 binding site agonists for the treatment of anxiety disorders
    Simon C Goodacre
    Department of Medicinal Chemistry, Merck Sharp Laboratory, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, UK
    J Med Chem 49:35-8. 2006
    ..The 7-trifluoromethylimidazopyrimidine 14g and the 7-propan-2-olimidazopyrimidine 14k are anxiolytic in both conditioned and unconditioned animal models of anxiety with minimal sedation observed at full BZ binding site occupancy...
  14. ncbi request reprint Comparison of lorazepam [7-chloro-5-(2-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one] occupancy of rat brain gamma-aminobutyric acid(A) receptors measured using in vivo [3H]flumazenil (8-fluoro 5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a]
    John R Atack
    Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom
    J Pharmacol Exp Ther 320:1030-7. 2007
    ....
  15. ncbi request reprint Contribution of specific binding to the central benzodiazepine site to the brain concentrations of two novel benzodiazepine site ligands
    Andrew Pike
    Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Harlow, UK
    Biopharm Drug Dispos 28:275-82. 2007
    ..These data suggest measured concentrations of compounds A and B in brain tissue are dependent on receptor expression with a minimal contribution from unbound and non-specifically bound compound...
  16. ncbi request reprint Differential contribution of GABA(A) receptor subtypes to the anticonvulsant efficacy of benzodiazepine site ligands
    Rosa L Fradley
    Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK
    J Psychopharmacol 21:384-91. 2007
    ....
  17. ncbi request reprint A pyridazine series of alpha2/alpha3 subtype selective GABA A agonists for the treatment of anxiety
    Richard T Lewis
    The Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, United Kingdom
    J Med Chem 49:2600-10. 2006
    ..These ligands are antagonists at the alpha1 subtype, with good CNS penetration and receptor occupancy, and excellent oral bioavailability...
  18. ncbi request reprint Discovery of imidazo[1,2-b][1,2,4]triazines as GABA(A) alpha2/3 subtype selective agonists for the treatment of anxiety
    Michael G N Russell
    J Med Chem 49:1235-8. 2006
    ..Compound 11 shows good bioavailability and half-life in preclinical species, and it is a nonsedating anxiolytic in both rat and squirrel monkey behavioral models...
  19. ncbi request reprint Rat pharmacokinetics and pharmacodynamics of a sustained release formulation of the GABAA alpha5-selective compound L-655,708
    John R Atack
    Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Eastwick Road, Harlow, Essex CM20 2QR, England
    Drug Metab Dispos 34:887-93. 2006
    ..In vivo binding experiments confirmed the selective occupancy of rat brain alpha5-over alpha1-, alpha2-, and alpha3-containing GABA(A) receptors...
  20. doi request reprint In vivo characterization and dynamic receptor occupancy imaging of TPA023B, an alpha 2/alpha 3/alpha 5 subtype selective gamma-aminobutyric acid-a partial agonist
    Koen Van Laere
    Division of Nuclear Medicine, K U Leuven, Belgium
    Biol Psychiatry 64:153-61. 2008
    ....
  21. ncbi request reprint The in vivo properties of pagoclone in rat are most likely mediated by 5'-hydroxy pagoclone
    John R Atack
    Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Neuropharmacology 50:677-89. 2006
    ..3-3mg/kg p.o.) also produced sedation. It is therefore likely that in rats 5'-hydroxy pagoclone mediates the majority of the pharmacological actions following pagoclone administration...
  22. pmc Selective labelling of diazepam-insensitive GABAA receptors in vivo using [3H]Ro 15-4513
    Luanda J Pym
    Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Br J Pharmacol 146:817-25. 2005
    ..e. DS plus DIS) [3H]Ro 15-4513 binding observed in the absence of lorazepam...
  23. ncbi request reprint TPA023 [7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine], an agonist selective for alpha2- and alpha3-containing GABAA receptors, is a nonsedating anxiolytic in rodents and primates
    John R Atack
    Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    J Pharmacol Exp Ther 316:410-22. 2006
    ..In summary, the novel alpha2/alpha3-selective efficacy profile of TPA023 translates into a nonsedating anxiolytic profile that is distinct from nonselective agonists...
  24. ncbi request reprint 3-phenyl-6-(2-pyridyl)methyloxy-1,2,4-triazolo[3,4-a]phthalazines and analogues: high-affinity gamma-aminobutyric acid-A benzodiazepine receptor ligands with alpha 2, alpha 3, and alpha 5-subtype binding selectivity over alpha 1
    Robert W Carling
    Department of Medicinal Chemistry, The Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    J Med Chem 47:1807-22. 2004
    ....
  25. doi request reprint Effects of SB-269970, a 5-HT7 receptor antagonist, in mouse models predictive of antipsychotic-like activity
    Ruggero Galici
    Johnson and Johnson Pharmaceutical Research and Development, LLC, 3210 Merryfield Row, San Diego, CA 92121, USA
    Behav Pharmacol 19:153-9. 2008
    ..Collectively, these results indicate that blockade of 5-HT7 receptors partially modulates glutamatergic and dopaminergic function and could be clinically useful for the treatment of positive symptoms of schizophrenia...
  26. ncbi request reprint Subtype-selective GABAergic drugs facilitate extinction of mouse operant behaviour
    Ciara McCabe
    School of Psychology, University of Ulster, Shore Road, BT37 0QB, Northern Ireland, Newtownabbey, UK
    Neuropharmacology 46:171-8. 2004
    ..These studies demonstrate that GABA-mediated processes are important during extinction of an appetitively motivated task, but only after the animals have experienced several extinction sessions...
  27. ncbi request reprint Anxioselective compounds acting at the GABA(A) receptor benzodiazepine binding site
    John R Atack
    Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Curr Drug Targets CNS Neurol Disord 2:213-32. 2003
    ..Nevertheless, efficacy selective compounds represent a novel approach to targeting specific subtypes of the GABA(A) receptor, the ultimate test of which will be evaluation in the clinic...
  28. ncbi request reprint Identification of a novel, selective GABA(A) alpha5 receptor inverse agonist which enhances cognition
    Mark S Chambers
    Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK
    J Med Chem 46:2227-40. 2003
    ....
  29. ncbi request reprint Enhanced learning and memory and altered GABAergic synaptic transmission in mice lacking the alpha 5 subunit of the GABAA receptor
    Neil Collinson
    Neuroscience Research Center, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, CM20 2QR, United Kingdom
    J Neurosci 22:5572-80. 2002
    ..These data suggest that alpha5-containing GABA(A) receptors play a key role in cognitive processes by controlling a component of synaptic transmission in the CA1 region of the hippocampus...
  30. ncbi request reprint 3-Heteroaryl-2-pyridones: benzodiazepine site ligands with functional delectivity for alpha 2/alpha 3-subtypes of human GABA(A) receptor-ion channels
    Ian Collins
    Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, CM20 2QR, United Kingdom
    J Med Chem 45:1887-900. 2002
    ....
  31. ncbi request reprint An orally bioavailable, functionally selective inverse agonist at the benzodiazepine site of GABAA alpha5 receptors with cognition enhancing properties
    Mark S Chambers
    Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK
    J Med Chem 47:5829-32. 2004
    ..It does not exhibit the convulsant, proconvulsant, or anxiogenic activity associated with nonselective GABA(A) inverse agonists...
  32. ncbi request reprint Selective, orally active gamma-aminobutyric acidA alpha5 receptor inverse agonists as cognition enhancers
    Francine Sternfeld
    The Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK
    J Med Chem 47:2176-9. 2004
    ..Compounds of this type may be useful in the symptomatic treatment of memory impairment associated with Alzheimer's disease and related dementias...
  33. ncbi request reprint 3,4-Dihydronaphthalen-1(2H)-ones: novel ligands for the benzodiazepine site of alpha5-containing GABAA receptors
    Helen J Szekeres
    Merck, Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Bioorg Med Chem Lett 14:2871-5. 2004
    ....
  34. ncbi request reprint A new pyridazine series of GABAA alpha5 ligands
    Monique B van Niel
    Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, United Kingdom
    J Med Chem 48:6004-11. 2005
    ..This paper will describe the evolution of 6 into a new series of ligands with nanomolar affinity and functional selectivity for GABAA alpha5 receptor subtypes...
  35. ncbi request reprint In vivo labelling of alpha5 subunit-containing GABA(A) receptors using the selective radioligand [(3)H]L-655,708
    John R Atack
    Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, England, UK
    Neuropharmacology 49:220-9. 2005
    ..These data therefore suggest that [(3)H]L-655,708 can be used to identify alpha5-containing GABA(A) receptors in vivo and that this ligand can be used to measure receptor occupancy of alpha5-selective ligands...
  36. ncbi request reprint The benzodiazepine binding site of GABA(A) receptors as a target for the development of novel anxiolytics
    John R Atack
    Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Expert Opin Investig Drugs 14:601-18. 2005
    ....
  37. pmc Anxiogenic properties of an inverse agonist selective for alpha3 subunit-containing GABA A receptors
    John R Atack
    Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Br J Pharmacol 144:357-66. 2005
    ....
  38. pmc Different GABAA receptor subtypes mediate the anxiolytic, abuse-related, and motor effects of benzodiazepine-like drugs in primates
    James K Rowlett
    Harvard Medical School, New England Primate Research Center, One Pine Hill Road, Box 9102, Southborough, MA 01772, USA
    Proc Natl Acad Sci U S A 102:915-20. 2005
    ..In contrast, stimulation of alpha1GABAA receptors is sufficient, but not necessary, for mediation of the abuse potential of these drugs...
  39. ncbi request reprint The proconvulsant effects of the GABAA alpha5 subtype-selective compound RY-080 may not be alpha5-mediated
    John R Atack
    Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, England
    Eur J Pharmacol 548:77-82. 2006
    ....
  40. ncbi request reprint Synthesis and biological evaluation of 3-heterocyclyl-7,8,9,10-tetrahydro-(7,10-ethano)-1,2,4-triazolo[3,4-a]phthalazines and analogues as subtype-selective inverse agonists for the GABA(A)alpha5 benzodiazepine binding site
    Leslie J Street
    Departments of Medicinal Chemistry, Biochemistry, and Pharmacology, Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    J Med Chem 47:3642-57. 2004
    ....
  41. ncbi request reprint 2,5-Dihydropyrazolo[4,3-c]pyridin-3-ones: functionally selective benzodiazepine binding site ligands on the GABAA receptor
    Andrew Mitchinson
    Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow CM20 2QR, UK
    Bioorg Med Chem Lett 14:3441-4. 2004
    ..2,5-Dihydropyrazolo[4,3-c]pyridin-3-ones are GABAA receptor benzodiazepine binding site ligands with functional selectivity for the alpha3 subtype over the alpha1 subtype. SAR studies to optimise this functional selectivity are described...
  42. ncbi request reprint Tricyclic pyridones as functionally selective human GABAA alpha 2/3 receptor-ion channel ligands
    James Crawforth
    Department of Medicinal Chemistry, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Bioorg Med Chem Lett 14:1679-82. 2004
    ..This investigation led to the identification of a high affinity, functionally selective, orally bioavailable benzodiazepine site ligand that demonstrated activity in rodent anxiolysis models and reduced sedation relative to diazepam...
  43. ncbi request reprint The novel gamma secretase inhibitor N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) reduces amyloid plaque deposition without evidence of notch-related pathology in the Tg2576 mouse
    Jonathan D Best
    Department of In Vivo Neuroscience, Merck Sharp and Dohme, Neurosciene Research Centre, Harlow, UK
    J Pharmacol Exp Ther 320:552-8. 2007
    ..An understanding of the mechanisms whereby MRK-560 shows differentiation between the APP and Notch proteolytic pathway of gamma-secretase should provide the basis for the next generation of gamma-secretase inhibitors...
  44. ncbi request reprint A comparative assessment of gamma-secretase activity in transgenic and non-transgenic rodent brain
    Julian L Goggi
    Department of In Vivo Neuroscience, The Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Essex CM20 2QR, UK
    J Neurosci Methods 157:246-52. 2006
    ..The data in the current paper indicate that this assay is able to measure the level of gamma-secretase activity in rodent species. Using this methodology will aid our understanding of physiological gamma-secretase function...
  45. ncbi request reprint 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
    Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Neuropharmacology 51:168-72. 2006
    ..0mg/kg). As expected, ex vivo binding can give an underestimation of receptor occupancy but this can be minimised by careful attention to the kinetics of unlabelled drug and radioligand...
  46. ncbi request reprint 2,3,7-Trisubstituted pyrazolo[1,5-d][1,2,4]triazines: functionally selective GABAA alpha3-subtype agonists
    Robert W Carling
    Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Harlow, Essex, CM20 2QR, UK
    Bioorg Med Chem Lett 16:3550-4. 2006
    ....
  47. ncbi request reprint In vivo characterization of Abeta(40) changes in brain and cerebrospinal fluid using the novel gamma-secretase inhibitor N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) in the rat
    Jonathan D Best
    Departmentsof In Vivo Neuroscience, The Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Harlow, Essex, United Kingdom
    J Pharmacol Exp Ther 317:786-90. 2006
    ....
  48. ncbi request reprint Imidazo[1,2-a]pyrimidines as functionally selective GABA(A) ligands
    Wesley P Blackaby
    Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Bioorg Med Chem Lett 16:1175-9. 2006
    ..SAR studies to optimize this functional selectivity are described...
  49. ncbi request reprint Pharmacokinetics and metabolism studies on (3-tert-butyl-7-(5-methylisoxazol-3-yl)-2-(1-methyl-1H-1,2,4-triazol-5-ylmethoxy) pyrazolo[1,5-d][1,2,4]triazine, a functionally selective GABA(A) alpha5 inverse agonist for cognitive dysfunction
    Philip Jones
    Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, CM20 2QR, UK
    Bioorg Med Chem Lett 16:872-5. 2006
    ..An unusual oxidation of the pyrazolo[1,5-d][1,2,4]triazine core to the corresponding pyrazolo[1,5-d][1,2,4]triazin-4(5H)-one scaffold by aldehyde oxidase has been observed...
  50. ncbi request reprint Pyrazolopyridinones as functionally selective GABAA ligands
    Wesley P Blackaby
    Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Bioorg Med Chem Lett 15:4998-5002. 2005
    ..SAR studies to optimize this functional selectivity are described...
  51. ncbi request reprint Development of subtype selective GABAA modulators
    Gerard R Dawson
    Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Essex CM20 1QR, England
    CNS Spectr 10:21-7. 2005
    ..Therefore, it may be possible to develop effective anxiolytic compounds that have a much reduced side-effect profile compared with existing drugs...
  52. ncbi request reprint 6,7-Dihydro-2-benzothiophen-4(5H)-ones: a novel class of GABA-A alpha5 receptor inverse agonists
    Mark S Chambers
    Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    J Med Chem 45:1176-9. 2002
    ..In particular, 6,6-dimethyl-3-(2-hydroxyethyl)thio-1-(thiazol-2-yl)-6,7-dihydro-2-benzothiophen-4(5H)-one (26) has been identified as a functionally selective GABA-A alpha5 inverse agonist...