MRK-409 (MK-0343), a GABAA receptor subtype-selective partial agonist, is a non-sedating anxiolytic in preclinical species but causes sedation in humans

Journal of Psychopharmacology

Volumn 25, Issue 3, 2011, Pages 314-328

  Atack, J R ^a   Wafford, K A ^a   Street, L J ^a   Dawson, G R ^a   Tye, S ^a   Van Laere, K ^b   Bormans, G ^b   Sanabria Bohorquez S M ^b   De Lepeleire, I ^c   De Hoon, J N ^d   Van Hecken, A ^d   Burns, H D ^b   McKernan, R M ^a   Murphy, M G ^b   Hargreaves, R J ^b  

^a NEUROSCIENCE RESEARCH CENTRE   (United Kingdom)

^b UNIVERSITY OF LEUVEN   (Belgium)

^c MERCK RESEARCH LABORATORIES   (United States)

^d Merck Sharp and Dohme   (Belgium)

Author keywords

benzodiazepine; GABAA receptor; non sedating anxiolytic; sedation; subtype selective

Indexed keywords

4 AMINOBUTYRIC ACID A RECEPTOR ALPHA1; 4 AMINOBUTYRIC ACID A RECEPTOR ALPHA3; 4 AMINOBUTYRIC ACID A RECEPTOR STIMULATING AGENT; 7 CYCLOBUTYL 6 (2 METHYL 2H 1,2,4 TRIAZOL 3 YLMETHOXY) 3 (2,6 DIFLUOROPHENYL) 1,2,4 TRIAZOLO[4,3 B]PYRIDAZINE; ANXIOLYTIC AGENT; BENZODIAZEPINE; CHLORDIAZEPOXIDE; DIAZEPAM; FLUMAZENIL; MK 0343; MRK 409; PLACEBO; UNCLASSIFIED DRUG;

ADULT; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANXIETY DISORDER; AREA UNDER THE CURVE; ARTICLE; BINDING AFFINITY; BINDING ASSAY; COMPETITIVE INHIBITION; CONTROLLED STUDY; DOSE RESPONSE; DROWSINESS; DRUG BINDING SITE; DRUG BLOOD LEVEL; DRUG DOSE ESCALATION; DRUG EFFICACY; DRUG PENETRATION; DRUG SAFETY; DRUG TOLERABILITY; DRUG UPTAKE; FATIGUE; HUMAN; IN VIVO STUDY; MALE; MAXIMUM PLASMA CONCENTRATION; MAXIMUM TOLERATED DOSE; MOUSE; NONHUMAN; POSITRON EMISSION TOMOGRAPHY; PRIORITY JOURNAL; RAT; SOMNOLENCE; TRANQUILIZING ACTIVITY;

ADOLESCENT; ADULT; ANIMALS; ANTI-ANXIETY AGENTS; ANXIETY; BINDING SITES; BRAIN; CHLORDIAZEPOXIDE; DISEASE MODELS, ANIMAL; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG EVALUATION, PRECLINICAL; GABA-A RECEPTOR AGONISTS; HETEROCYCLIC COMPOUNDS WITH 4 OR MORE RINGS; HUMANS; HYDROCARBONS, FLUORINATED; MALE; MICE; MIDDLE AGED; POSITRON-EMISSION TOMOGRAPHY; PROTEIN BINDING; PROTEIN SUBUNITS; RATS; RATS, SPRAGUE-DAWLEY; SAIMIRI; SPECIES SPECIFICITY; TISSUE DISTRIBUTION; YOUNG ADULT;

EID: 79952149335     PISSN: 02698811     EISSN: 14617285     Source Type: Journal    
DOI: 10.1177/0269881109354927     Document Type: Article

References (44)

1. Atack JR (2003) Anxioselective compounds acting at the GABAA receptor benzodiazepine binding site. Curr Drug Targets CNS Neurol Disord 2: 213-232.
2. Atack JR (2005) The benzodiazepine binding site of GABAA receptors as a target for the development of novel anxiolytics. Expert Opin Investig Drugs 14: 601-618. (Pubitemid 40790282)
3. Atack JR, Hallett D., Tye S., et al. (2010) Preclinical and clinical pharmacology of TPA023B, a GABAA receptor α2/α3 subtype-selective agonist. Accompanying article.
4. Atack JR, Hutson PH, Collinson N., et al. (2005) Anxiogenic properties of an inverse agonist selective for α3 subunit-containing GABAA receptors. Br J Pharmacol 144: 357-366. (Pubitemid 40313682)
5. Atack JR, Smith AJ, Emms F., McKernan RM (1999) Regional differences in the inhibition of mouse in vivo [3H]Ro 15-1788 binding reflect selectivity for α1 versus α2 and α3 subunit-containing GABAA receptors. Neuropsychopharmacology 20: 255-262. (Pubitemid 29067404)
6. Atack JR, Wafford KA, Tye SJ, et al. (2006) 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 α2- and α3-containing GABAA receptors, is a nonsedating anxiolytic in rodents and primates. J Pharmacol Exp Ther 316: 410-422. (Pubitemid 41832621)
7. Ballard TM, Knoflach F., Prinssen E., et al. (2009) RO4938581, a novel cognitive enhancer acting at GABAA α5 subunit-containing receptors. Psychopharmacology 202: 207-223.
8. Berezhnoy D., Gravielle MC, Downing S., et al. (2008) Pharmacological properties of DOV 315,090, an ocinaplon metabolite. BMC Pharmacol 8: 11.
9. Brown N., Kerby J., Bonnert TP, Whiting PJ, Wafford KA (2002) Pharmacological characterization of a novel cell line expressing human α4?3? GABAA receptors. Br J Pharmacol 136: 965-974.
10. Carling RW, Madin A., Guiblin A., et al. (2005) 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 ?-aminobutyric acidA (GABAA) α2/α3-subtype selective agonist that exhibits potent anxiolytic activity but is not sedating in animal models. J Med Chem 48: 7089-7092. (Pubitemid 41743620)
11. Chambers MS, Atack JR, Carling RW, et al. (2004) An orally bioavailable, functionally selective inverse agonist at the benzodiazepine site of GABAA α5 receptors with cognition enhancing properties. J Med Chem 47: 5829-5832. (Pubitemid 39507328)
12. Dawson GR, Tricklebank MD (1995) Use of the elevated plus maze in the search for novel anxiolytic agents. Trends Pharmacol Sci 16: 33-36.
13. Dawson GR, Curnow R., Bayley P., Rambridge A., Tricklebank MD (1994) Lack of effect of flumazenil and CGS 8216 on the anxiolytic-like properties of loreclezole. Eur J Pharmacol 252: 325-328. (Pubitemid 24053702)
14. Dawson GR, Maubach KA, Collinson N., et al. (2006) An inverse agonist selective for α5 subunit-containing GABAA receptors enhances cognition. J Pharmacol Exp Ther 316: 1335-1345. (Pubitemid 43345310)
15. De Haas SL, de Visser SJ, van der Post JP, et al. (2007) Pharmacodynamic and pharmacokinetic effects of TPA023, a GABAA α2,3 subtype-selective agonist, compared to lorazepam and placebo in healthy volunteers. J Psychopharmacol 21: 374-383. (Pubitemid 47077294)
16. De Haas SL, de Visser SJ, van der Post JP, et al. (2008) Pharmacodynamic and pharmacokinetic effects of MK-0343, a GABAA α2,3 subtype selective agonist, compared to lorazepam and placebo in healthy male volunteers. J Psychopharmacol 22: 24-32.
17. De Haas SL, Franson KL, Schmitt JAJ, et al. (2009) The pharmacokinetic and pharmacodynamic effects of SL65.1498, a GABAA α2,3 selective agonist, in comparison with lorazepam in healthy volunteers. J Psychopharmacol 23: 625-632.
18. De Visser SJ, van der Post JP, de Waal PP, Cornet F., Cohen AF, van Gerven JMA (2003) Biomarkers for the effects of benzodiazepines in healthy volunteers. Br J Clin Pharmacol 55: 39-50. (Pubitemid 36110838)
19. Dias R., Sheppard WFA, Fradley RL, et al. (2005) Evidence for a significant role of α3-containing GABAA receptors in mediating the anxiolytic effects of benzodiazepines. J Neurosci 25: 10682-10688. (Pubitemid 41681916)
20. Griebel G., Perrault G., Simiand J., et al. (2001) SL651498: An anxioselective compound with functional selectivity for α2- and α3-containing ?-aminobutyric acidA (GABAA) receptors. J Pharmacol Exp Ther 298: 753-768. (Pubitemid 32673429)
21. Hadingham KL, Garrett EM, Wafford, KA, et al. (1996) Cloning of cDNAs encoding the human ?-aminobutyric acid type A receptor α6 subunit and characterization of the pharmacology of α6-containing receptors. Mol Pharmacol 49: 253-259. (Pubitemid 26066111)
22. Hadingham KL, Wingrove P., Le Bourdelles B., Palmer KJ, Ragan CI, Whiting PJ (1993) Cloning of cDNA sequences encoding human α2 and α3 ?-aminobutyric acidA receptor subunits and characterization of the benzodiazepine pharmacology of recombinant α1-, α2-, α3-, and α5-containing human ?-aminobutyric acidA receptors. Mol Pharmacol 43: 970-975. (Pubitemid 23178875)
23. Krause JE, Matchett M., Crandall M., Yu J., Baltazar C., Brodbeck RM, Kehne JH, Maynard GD, Shaw KR, Chenard BL, Hutchison AJ, Xie L. and Yu W. (2007) I. Preclinical characterization in vitro of NG2-73 as a potent and selective partial allosteric activator of GABAA receptors with predominant efficacy at the α3 subunit. Program No. AAA26. 2007 Neuroscience Meeting Planner. San Diego, CA: Society for Neuroscience, 2007. Online.
24. Lippa A., Czobor P., Stark J., et al. (2005) Selective anxiolysis produced by ocinaplon, a GABAA receptor modulator. Proc Natl Acad Sci USA 102: 7380-7385. (Pubitemid 40696386)
25. Löw K., Crestani F., Keist R., et al. (2000) Molecular and neuronal substrate for the selective attenuation of anxiety. Science 290: 131-134.
26. McKernan RM, Whiting PJ (1996) Which GABAA-receptor subtypes really occur in the brain ? Trends Neurosci 19: 139-143.
27. McKernan RM, Rosahl TW, Reynolds DS, et al. (2000) Sedative but not anxiolytic properties of benzodiazepines are mediated by the GABAA receptor α1 subtype. Nature Neurosci 3: 587-592. (Pubitemid 30332078)
28. Maubach KA (2003) GABAA receptor subtype selective cognition enhancers. Curr Drug Targets CNS Neurol Disord 2: 233-239.
29. Mirza NR, Larsen JS, Mathiasen C., et al. (2008) NS11394 [3'-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2-carbonitrile], a unique subtype-selective GABAA receptor positive allosteric modulator: in vitro actions, pharmacokinetic properties and in vivo anxiolytic efficacy. J Pharmacol Exp Ther 327: 954-968.
30. Morris HV, Dawson GR, Reynolds DS, Atack JR, Stephens DN (2006) Both α2 and α3 GABAA receptor subtypes mediate the anxiolytic properties of benzodiazepine site ligands in the conditioned emotional response paradigm. Eur J Neurosci 23: 2495-2504. (Pubitemid 43742880)
31. Munro G., Lopez-Garcia JA, Rivera-Arconada I., et al. (2008) Comparison of the novel subtype-selective GABAA receptor-positive allosteric modulator NS11394 [3'-[5-(1-hydroxy-1-methyl-ethyl)-benzoimidazol-1-yl]-biphenyl-2- carbonitrile] with diazepam, zolpidem, bretazenil, and gaboxadol in rat models of inflammatory and neuropathic pain. J Pharmacol Exp Ther 327: 969-981.
32. Popik P., Kostakis E., Krawczyk M., et al. (2006) The anxioselective agent 7-(2-chloropyridin-4-yl)pyrazolo-[1,5-a]-pyrimidin-3-yl](pyridin-2-yl) methanone (DOV 51892) is more efficacious than diazepam at enhancing GABA-gated currents at α1 subunit-containing GABAA receptors. J Pharmacol Exp Ther 319: 1244-1252.
33. Rowlett JK, Platt DM, Lelas S., Atack JR, Dawson GR (2005) Different GABAA receptor subtypes mediate the anxiolytic, abuse-related, and motor effects of benzodiazepine-like drugs in primates. Proc Natl Acad Sci USA 102: 915-920. (Pubitemid 40282765)
34. Rudolph U., Möhler H. (2004) Analysis of GABAA receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics. Annu Rev Pharmacol Toxicol 44: 475-498. (Pubitemid 38263850)
35. Rudolph U., Crestani F., Benke D., et al. (1999) Benzodiazepine actions mediated by specific ?-aminobutyric acidA receptor subtypes. Nature 401: 796-800.
36. Salmi E., Aalto S., Hirvonen J., et al. (2008) Measurement of GABAA receptor binding in vivo with [11C]Flumazenil: a test-retest study in healthy subjects. Neuroimage 41: 260-269.
37. Savi? MM, Huang S., Furtmüller R., et al. (2008) Are GABAA receptors containing α5 subunits contributing to the sedative properties of benzodiazepine site agonists ? Neuropsychopharmacology 33: 332-339. (Pubitemid 350243345)
38. Sieghart W. (2006) Structure, pharmacology, and function of GABAA receptor subtypes. Adv Pharmacol 54: 231-263.
39. Sieghart W., Sperk G. (2002) Subunit composition, distribution and function of GABAA receptor subtypes. Curr Top Med Chem 2: 795-816.
40. Simon J., Wakimoto H., Fujita N., Lalande M., Barnard EA (2004) Analysis of the set of GABAA receptor genes in the human genome. J Biol Chem 279: 41422-41435. (Pubitemid 39313583)
41. Van Laere K., Bormans G., Sanabria-Bohórquez SM, et al. (2008) In vivo characterization and dynamic receptor occupancy imaging of TPA023B, an α2/α3/α5 subtype selective ?-aminobutyric acid-A partial agonist. Biol Psychiatry 64: 153-161.
42. Van Steveninck AL, Gieschke R., Schoemaker RC, et al. (1996) Pharmacokinetic and pharmacodynamic interactions of bretazenil and diazepam with alcohol. Br J Clin Pharmacol 41: 565-573. (Pubitemid 26186135)
43. Wafford KA, Thompson SA, Thomas D., Sikela J., Wilcox AS, Whiting PJ (1996) Functional characterization of human ?-aminobutyric acidA receptors containing the α4 subunit. Mol Pharmacol 50: 670-678. (Pubitemid 26303601)
44. Wieland HA, Lüddens H., Seeburg PH (1992) A single histidine in GABAA receptors is essential for benzodiazepine agonist binding. J Biol Chem 267: 1426-1429.