K A Wafford

Summary

Affiliation: Merck Research Laboratories
Country: USA

Publications

  1. ncbi request reprint Functional characterization of human gamma-aminobutyric acidA receptors containing the alpha 4 subunit
    K A Wafford
    Merck Sharp and Dohme Research Laboratories, Harlow, Essex, UK
    Mol Pharmacol 50:670-8. 1996
  2. ncbi request reprint Gaboxadol--a new awakening in sleep
    Keith A Wafford
    Merck, Sharp and Dohme, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Curr Opin Pharmacol 6:30-6. 2006
  3. ncbi request reprint Differentiating the role of gamma-aminobutyric acid type A (GABAA) receptor subtypes
    K A Wafford
    Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Biochem Soc Trans 32:553-6. 2004
  4. ncbi request reprint GABAA receptor subtypes: any clues to the mechanism of benzodiazepine dependence?
    Keith A Wafford
    Department of Molecular and Cellular Neuroscience, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Harlow, Essex CM20 2QR, UK
    Curr Opin Pharmacol 5:47-52. 2005
  5. ncbi request reprint Cloning of cDNAs encoding the human gamma-aminobutyric acid type A receptor alpha 6 subunit and characterization of the pharmacology of alpha 6-containing receptors
    K L Hadingham
    Merck Sharp and Dohme Research Laboratories, Harlow, Essex, UK
    Mol Pharmacol 49:253-9. 1996
  6. ncbi request reprint Overexpression of the GABA(A) receptor epsilon subunit results in insensitivity to anaesthetics
    S A Thompson
    Merck Sharp and Dohme Research Laboratories, Terlings Park, Harlow CM20 2QR, UK
    Neuropharmacology 43:662-8. 2002
  7. pmc theta, a novel gamma-aminobutyric acid type A receptor subunit
    T P Bonnert
    Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Eastwick Road, Harlow, Essex CM20 2QR, England, UK
    Proc Natl Acad Sci U S A 96:9891-6. 1999
  8. ncbi request reprint Differences in agonist/antagonist binding affinity and receptor transduction using recombinant human gamma-aminobutyric acid type A receptors
    B Ebert
    Department of Pharmacology, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, England
    Mol Pharmacol 52:1150-6. 1997
  9. doi request reprint In vitro and in vivo properties of 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 (MRK-016), a GABAA receptor alpha5 subtype-selective inverse agonist
    John R Atack
    Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom
    J Pharmacol Exp Ther 331:470-84. 2009
  10. pmc Pharmacological characterization of a novel cell line expressing human alpha(4)beta(3)delta GABA(A) receptors
    N Brown
    Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Br J Pharmacol 136:965-74. 2002

Detail Information

Publications67

  1. ncbi request reprint Functional characterization of human gamma-aminobutyric acidA receptors containing the alpha 4 subunit
    K A Wafford
    Merck Sharp and Dohme Research Laboratories, Harlow, Essex, UK
    Mol Pharmacol 50:670-8. 1996
    ..These experiments reveal a unique pharmacology for alpha 4-containing receptors with some similarities to both alpha 6- and alpha 1-containing receptors...
  2. ncbi request reprint Gaboxadol--a new awakening in sleep
    Keith A Wafford
    Merck, Sharp and Dohme, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Curr Opin Pharmacol 6:30-6. 2006
    ..This unique mechanism has contributed to our increased understanding of sleep mechanisms, and targeting of this system offers potential advantages over existing insomnia treatments...
  3. ncbi request reprint Differentiating the role of gamma-aminobutyric acid type A (GABAA) receptor subtypes
    K A Wafford
    Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Biochem Soc Trans 32:553-6. 2004
    ..This technique together with the development of subtype-selective compounds facilitates our understanding of the roles played by each receptor subtype...
  4. ncbi request reprint GABAA receptor subtypes: any clues to the mechanism of benzodiazepine dependence?
    Keith A Wafford
    Department of Molecular and Cellular Neuroscience, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Harlow, Essex CM20 2QR, UK
    Curr Opin Pharmacol 5:47-52. 2005
    ..In addition, the involvement of GABA(A) receptors in this phenomenon is leading to a greater understanding of other drugs such as alcohol and opiates...
  5. ncbi request reprint Cloning of cDNAs encoding the human gamma-aminobutyric acid type A receptor alpha 6 subunit and characterization of the pharmacology of alpha 6-containing receptors
    K L Hadingham
    Merck Sharp and Dohme Research Laboratories, Harlow, Essex, UK
    Mol Pharmacol 49:253-9. 1996
    ..This observation demonstrates definitively that efficacy of benzodiazepine compounds cannot be generalized across receptor subtypes and may also help explain some of the behavioral effects that have been reported for these compounds...
  6. ncbi request reprint Overexpression of the GABA(A) receptor epsilon subunit results in insensitivity to anaesthetics
    S A Thompson
    Merck Sharp and Dohme Research Laboratories, Terlings Park, Harlow CM20 2QR, UK
    Neuropharmacology 43:662-8. 2002
    ....
  7. pmc theta, a novel gamma-aminobutyric acid type A receptor subunit
    T P Bonnert
    Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Eastwick Road, Harlow, Essex CM20 2QR, England, UK
    Proc Natl Acad Sci U S A 96:9891-6. 1999
    ..This subunit has a unique distribution, with studies so far suggesting significant expression within monoaminergic neurons of both human and monkey brain...
  8. ncbi request reprint Differences in agonist/antagonist binding affinity and receptor transduction using recombinant human gamma-aminobutyric acid type A receptors
    B Ebert
    Department of Pharmacology, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, England
    Mol Pharmacol 52:1150-6. 1997
    ..It is concluded that the GABAA receptor mechanisms transducing binding into physiological response, but not the binding per se, is dependent on the receptor subunit composition...
  9. doi request reprint In vitro and in vivo properties of 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 (MRK-016), a GABAA receptor alpha5 subtype-selective inverse agonist
    John R Atack
    Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom
    J Pharmacol Exp Ther 331:470-84. 2009
    ..5 mg, which, along with its variable human pharmacokinetics, precluded its further development...
  10. pmc Pharmacological characterization of a novel cell line expressing human alpha(4)beta(3)delta GABA(A) receptors
    N Brown
    Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Br J Pharmacol 136:965-74. 2002
    ..With its restricted distribution within the brain and unique pharmacology this receptor may play an important role in the action of neurosteroids and anaesthetics. British Journal of Pharmacology (2002) 136, 965-974..
  11. ncbi request reprint Molecular and functional diversity of the expanding GABA-A receptor gene family
    P J Whiting
    Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, England, UK
    Ann N Y Acad Sci 868:645-53. 1999
    ..The structure, function, and distribution of theta-containing receptors, and receptors containing the recently reported epsilon subunit, are described...
  12. ncbi request reprint Loss of the major GABA(A) receptor subtype in the brain is not lethal in mice
    C Sur
    Neuroscience Research Center, Merck Sharp and Dohme Research Laboratories, Harlow, Essex, CM20 2QR, United Kingdom
    J Neurosci 21:3409-18. 2001
    ..Our data confirm that alpha1beta2gamma2 is the major GABA(A) receptor subtype in the murine brain and demonstrate that, surprisingly, the loss of this receptor subtype is not lethal...
  13. ncbi request reprint Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABA(A) receptor alpha1 subtype
    R M McKernan
    Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Nat Neurosci 3:587-92. 2000
    ..This finding suggests ways to improve anxiolytics and to develop drugs for other neurological disorders based on their specificity for GABA(A) receptor subtypes in distinct neuronal circuits...
  14. 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
    ....
  15. 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...
  16. ncbi request reprint Expression and pharmacology of human GABAA receptors containing gamma 3 subunits
    K L Hadingham
    Merch Sharp and Dohme Research Laborotories, Neuroscience Research Centre Harlow, Essex, UK
    Eur J Pharmacol 291:301-9. 1995
    ..Both the EC50 and efficacy of benzodiazepine site ligands were influenced by the type of gamma subunit coexpressed with alpha 1 and beta 2...
  17. ncbi request reprint Effect of alpha subunit on allosteric modulation of ion channel function in stably expressed human recombinant gamma-aminobutyric acid(A) receptors determined using (36)Cl ion flux
    A J Smith
    Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom
    Mol Pharmacol 59:1108-18. 2001
    ..The rank order of potentiation for pregnanolone was alpha5 > alpha2 > alpha3 = alpha4 > alpha1, for loreclezole alpha1 = alpha2 = alpha3 > alpha5 > alpha4, and for pentobarbital alpha4 = alpha5 = alpha2 > alpha1 = alpha3...
  18. doi request reprint Preclinical and clinical pharmacology of TPA023B, a GABAA receptor α2/α3 subtype-selective partial agonist
    J R Atack
    Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Harlow, UK
    J Psychopharmacol 25:329-44. 2011
    ....
  19. ncbi request reprint Sedation and anesthesia mediated by distinct GABA(A) receptor isoforms
    David S Reynolds
    Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Harlow, Essex CM20 2QR, United Kingdom
    J Neurosci 23:8608-17. 2003
    ..These findings show that anesthesia and sedation are mediated by distinct GABA(A) receptor subtypes...
  20. 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...
  21. 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...
  22. ncbi request reprint An inverse agonist selective for alpha5 subunit-containing GABAA receptors enhances cognition
    G R Dawson
    Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Terlings Park, Eastwick Rd, Harlow, Essex CM20 2QR, UK
    J Pharmacol Exp Ther 316:1335-45. 2006
    ..Together, these data suggest that the GABA(A) alpha5-subtype provides a novel target for the development of selective inverse agonists with utility in the treatment of disorders associated with a cognitive deficit...
  23. ncbi request reprint N-Methyl-D-aspartate receptor subtype-selectivity of homoquinolinate: an electrophysiological and radioligand binding study using both native and recombinant receptors
    Sarah Grimwood
    Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK
    J Neurochem 82:794-800. 2002
    ..In contrast to an autoradiographical study, these radioligand binding and electrophysiological experiments suggest that homoquinolinate is not highly selective for NR2B-containing receptors...
  24. doi request reprint Novel compounds selectively enhance delta subunit containing GABA A receptors and increase tonic currents in thalamus
    K A Wafford
    Department of Molecular and Cellular Neuroscience, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Harlow, United Kingdom
    Neuropharmacology 56:182-9. 2009
    ..Furthermore, these drugs may be valuable in elucidating the physiological and pathophysiological roles played by these extrasynaptic GABA(A) receptors...
  25. pmc Salicylidene salicylhydrazide, a selective inhibitor of beta 1-containing GABAA receptors
    S A Thompson
    Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex
    Br J Pharmacol 142:97-106. 2004
    ..The importance of threonine 255 and isoleucine 308 within the beta1 subunit and the lack of interaction with a range of GABA(A) receptor modulators suggests that SCS is interacting at a previously unidentified site...
  26. 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
    ....
  27. pmc Activity of chlormethiazole at human recombinant GABA(A) and NMDA receptors
    Marcello Usala
    Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR
    Br J Pharmacol 140:1045-50. 2003
    ..IC50's were approximately 500 microm that likely exceed the therapeutic dose range for chlormethiazole, indicating that the primary mechanism of the compounds in vivo activity is via GABAA receptors...
  28. ncbi request reprint Anticonvulsant and adverse effects of avermectin analogs in mice are mediated through the gamma-aminobutyric acid(A) receptor
    G R Dawson
    Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex, United Kingdom
    J Pharmacol Exp Ther 295:1051-60. 2000
    ..Because both anticonvulsant activity and toxicity correlated best with activity at GABA(A) receptors, it is unlikely that these effects can be separated, which may contraindicate the potential use of avermectins as anticonvulsants...
  29. 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...
  30. doi request reprint MRK-409 (MK-0343), a GABAA receptor subtype-selective partial agonist, is a non-sedating anxiolytic in preclinical species but causes sedation in humans
    J R Atack
    Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Harlow, UK
    J Psychopharmacol 25:314-28. 2011
    ..Thus, the preclinical non-sedating anxiolytic profile of MRK-409 did not translate into humans and further development of this compound was halted...
  31. ncbi request reprint Neuronally restricted RNA splicing regulates the expression of a novel GABAA receptor subunit conferring atypical functional properties [corrected; erratum to be published]
    P J Whiting
    Neuroscience Research Centre, Merck Sharp and Dohme Research Laboratories, Harlow, Essex CM20 2QR, United Kingdom
    J Neurosci 17:5027-37. 1997
    ....
  32. 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...
  33. 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
    ....
  34. 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...
  35. 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...
  36. 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...
  37. ncbi request reprint A genetically modified mouse model probing the selective action of ifenprodil at the N-methyl-D-aspartate type 2B receptor
    Thomas W Rosahl
    Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Mol Cell Neurosci 33:47-56. 2006
    ..The NR2B KI mice exhibited normal locomotor activity making this ifenprodil-insensitive mouse model a valuable tool to test the specificity of NR2B selective antagonists in vivo...
  38. 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...
  39. ncbi request reprint NR2B-selective N-methyl-D-aspartate antagonists: synthesis and evaluation of 5-substituted benzimidazoles
    John A McCauley
    Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
    J Med Chem 47:2089-96. 2004
    ..Benzimidazole 37a shows excellent activity in the carrageenan-induced mechanical hyperalgesia assay in rats as well as good pharmacokinetic behavior in dogs...
  40. ncbi request reprint Novel N1-(benzyl)cinnamamidine derived NR2B subtype-selective NMDA receptor antagonists
    Neil R Curtis
    Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, The Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Bioorg Med Chem Lett 13:693-6. 2003
    ..The 2-methoxybenzyl compound 1h had approximately 1,000-fold lower IC(50) in NR2B than NR2A-containing cells. Replacement of the styryl unit by 2-naphthyl was well tolerated...
  41. 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
    ....
  42. 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
    ....
  43. ncbi request reprint Tracazolate reveals a novel type of allosteric interaction with recombinant gamma-aminobutyric acid(A) receptors
    Sally Anne Thompson
    Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Essex, United Kingdom
    Mol Pharmacol 61:861-9. 2002
    ....
  44. ncbi request reprint Mechanism of alpha-subunit selectivity of benzodiazepine pharmacology at gamma-aminobutyric acid type A receptors
    Peter B Wingrove
    Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Essex CM20 2QR, Harlow, UK
    Eur J Pharmacol 437:31-9. 2002
    ....
  45. 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...
  46. 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...
  47. 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
    ....
  48. ncbi request reprint N-(indol-3-ylglyoxylyl)piperidines: high affinity agonists of human GABA-A receptors containing the alpha1 subunit
    I Collins
    Department of Medicinal Chemistry, Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, UK
    Bioorg Med Chem Lett 10:1381-4. 2000
    ..All three receptor subtypes discriminate substantially between the two enantiomers of the chiral ligand 10...
  49. ncbi request reprint The role of GABAbeta2 subunit-containing receptors in mediating the anticonvulsant and sedative effects of loreclezole
    James O Groves
    Merck, Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Terlings Park, Eastwick Road, Harlow, Essex CM20 2QR, UK
    Eur J Neurosci 24:167-74. 2006
    ..These results suggest that the majority of the sedative effects and a significant proportion of the anticonvulsant efficacy of loreclezole are mediated via beta2-containing GABA(A) receptors...
  50. ncbi request reprint Role of the beta subunit in determining the pharmacology of human gamma-aminobutyric acid type A receptors
    K L Hadingham
    Merck Sharp and Dohme Research Laboratories, Harlow, Essex, England
    Mol Pharmacol 44:1211-8. 1993
    ..These data suggest that the beta subunit does not significantly influence the benzodiazepine, barbiturate, or steriod site pharmacologies of human GABAA receptor subtypes...
  51. ncbi request reprint New directions in kinetic high information content assays
    Peter B Simpson
    Automated Imaging and Electrophysiology Group, Department of Molecular and Cellular Neuroscience, Neuroscience Research Centre, Merck Sharp and Dohme, Terlings Park, Harlow, Essex CM20 2QR, UK
    Drug Discov Today 11:237-44. 2006
  52. ncbi request reprint Gamma-aminobutyric acid type A receptor beta 2 subunit mediates the hypothermic effect of etomidate in mice
    Jennifer Cirone
    Merck Sharp and Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom
    Anesthesiology 100:1438-45. 2004
    ..Because most clinically used anesthetics produce hypothermia, the effect of this mutation on core body temperature was investigated...
  53. doi request reprint Emerging anti-insomnia drugs: tackling sleeplessness and the quality of wake time
    Keith A Wafford
    Eli Lilly UK, Erl Wood Manor, Windlesham, Surrey GU20 6PH, UK
    Nat Rev Drug Discov 7:530-40. 2008
    ....
  54. pmc The expression of GABAA beta subunit isoforms in synaptic and extrasynaptic receptor populations of mouse dentate gyrus granule cells
    Murray B Herd
    Neurosciences Institute, Division of Pathology and Neuroscience, University of Dundee, Ninewells Hospital and Medical School, Dundee DD1 9SY, UK
    J Physiol 586:989-1004. 2008
    ..The unambiguous identification of these distinct pools of synaptic and extrasynaptic GABA(A) receptors should aid our understanding of how they act in harmony, to regulate hippocampal signalling in health and disease...
  55. ncbi request reprint A disubstituted succinamide is a potent sodium channel blocker with efficacy in a rat pain model
    Birgit T Priest
    Department of Ion Channels, Merck Research Laboratories, Rahway, New Jersey 07065, USA
    Biochemistry 43:9866-76. 2004
    ..On the basis of these findings, BPBTS represents a structurally novel and potent sodium channel blocker that may be used as a template for the development of analgesic agents...
  56. ncbi request reprint The delta subunit of gamma-aminobutyric acid type A receptors does not confer sensitivity to low concentrations of ethanol
    Cecilia M Borghese
    The University of Texas at Austin, Waggoner Center for Alcohol and Addiction Research, 1 University Station A4800, Austin, TX 78712 0159, USA
    J Pharmacol Exp Ther 316:1360-8. 2006
    ..This suggests that as yet unidentified factors may play a critical role in the ethanol effects on delta-containing GABA(A)Rs...
  57. ncbi request reprint Treating insomnia: Current and investigational pharmacological approaches
    Bjarke Ebert
    Department of Electrophysiology, H Lundbeck A S, Ottiliavej 9, DK 2500 Valby, Copenhagen, Denmark
    Pharmacol Ther 112:612-29. 2006
    ....
  58. ncbi request reprint Orally efficacious NR2B-selective NMDA receptor antagonists
    Christopher F Claiborne
    Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA
    Bioorg Med Chem Lett 13:697-700. 2003
    ..Compound 31 is orally active in a carrageenan-induced rat hyperalgesia model of pain and shows no motor coordination side effects...
  59. 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...
  60. ncbi request reprint Selective enhancement of tonic GABAergic inhibition in murine hippocampal neurons by low concentrations of the volatile anesthetic isoflurane
    Valerie B Caraiscos
    Institute of Medical Science, University of Toronto, Toronto, Ontario M5S 1A8, Canada
    J Neurosci 24:8454-8. 2004
    ..These studies suggest that an increased tonic inhibition in the hippocampus may contribute to amnestic properties of volatile anesthetics...
  61. ncbi request reprint Extrasynaptic GABAA receptors of thalamocortical neurons: a molecular target for hypnotics
    Delia Belelli
    Neurosciences Institute, Division of Pathology and Neuroscience, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, United Kingdom
    J Neurosci 25:11513-20. 2005
    ..Collectively, these findings suggest that enhancement of extrasynaptic inhibition in the thalamus may contribute to the distinct sleep EEG profiles of etomidate and THIP compared with zolpidem...
  62. pmc Tonic inhibition in mouse hippocampal CA1 pyramidal neurons is mediated by alpha5 subunit-containing gamma-aminobutyric acid type A receptors
    Valerie B Caraiscos
    Institute of Medical Science, Department of Anesthesia, University of Toronto, Toronto, ON, Canada M5S 1A8
    Proc Natl Acad Sci U S A 101:3662-7. 2004
    ....
  63. pmc Thymol, a constituent of thyme essential oil, is a positive allosteric modulator of human GABA(A) receptors and a homo-oligomeric GABA receptor from Drosophila melanogaster
    Caroline M Priestley
    Department of Pharmaceutical and Biological Chemistry, The School of Pharmacy, 29 39 Brunswick Square, London WC1N 1AX
    Br J Pharmacol 140:1363-72. 2003
    ..These data suggest that thymol potentiates GABAA receptors through a previously unidentified binding site...
  64. ncbi request reprint Pharmacology of GABA(A) receptors exhibiting different levels of spontaneous activity
    Martin Mortensen
    Department of Pharmacology, The Danish University of Pharmaceutical Sciences, 2 Universitetsparken, DK 2100 Copenhagen, Denmark
    Eur J Pharmacol 476:17-24. 2003
    ..These novel findings indicate that the potency and efficacy of ligands acting on GABA(A) receptors are highly dependent on the level of spontaneous activity of the receptor...
  65. ncbi request reprint The pharmacology of spontaneously open alpha 1 beta 3 epsilon GABA A receptor-ionophores
    Gábor Maksay
    Department of Molecular Pharmacology, Chemical Research Center, Hungarian Academy of Sciences, P O Box 17, H 1525, Budapest, Hungary
    Neuropharmacology 44:994-1002. 2003
    ..In conclusion, spontaneously active alpha(1)beta(3) epsilon GABA(A) receptors can be potentiated and blocked by GABAergic agents within a broad range of efficacy...
  66. 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...
  67. ncbi request reprint Alpha5GABAA receptors mediate the amnestic but not sedative-hypnotic effects of the general anesthetic etomidate
    Victor Y Cheng
    Institute of Medical Science, Division of Neurology, Department of Medicine, University of Toronto, Toronto, Ontario, M5S 1A8, Canada
    J Neurosci 26:3713-20. 2006
    ..Thus, the amnestic and sedative-hypnotic properties of etomidate can be dissociated on the basis of GABAAR subtype pharmacology...