A multifaceted GABAA receptor modulator: Functional properties and mechanism of action of the sedative-hypnotic and recreational drug methaqualone (Quaalude)

Molecular Pharmacology

Volumn 88, Issue 2, 2015, Pages 401-420

  Hammer, Harriet ^a   Bader, Benjamin M ^b   Ehnert, Corina ^b   Bundgaard, Christoffer ^c   Bunch, Lennart ^a   Hoestgaard Jensen, Kirsten ^a   Schroeder, Olaf H U ^b   Bastlund, Jesper F ^c   Gramowski Voß, Alexandra ^b   Jensen, Anders A ^a  

^a UNIVERSITY OF COPENHAGEN   (Denmark)

^b NEUROPROOF GMBH   (Germany)

^c H LUNDBECK A S   (Denmark)

Author keywords

[No Author keywords available]

Indexed keywords

4 AMINOBUTYRIC ACID A RECEPTOR; 5,5 DIMETHYL 2 MORPHOLINEACETIC ACID; ETOMIDATE; METHAQUALONE; NEUROTRANSMITTER RECEPTOR; NEUROTRANSMITTER TRANSPORTER; HYPNOTIC SEDATIVE AGENT; STREET DRUG;

ALLOSTERISM; ANIMAL CELL; ANIMAL EXPERIMENT; ARTICLE; BINDING SITE; CENTRAL NERVOUS SYSTEM; CONTROLLED STUDY; DRUG MECHANISM; FEMALE; FRONTAL CORTEX; MALE; MOUSE; NONHUMAN; OOCYTE; PRIORITY JOURNAL; PROTEIN EXPRESSION; XENOPUS LAEVIS; ANIMAL; BRAIN; CHEMISTRY; DRUG EFFECTS; GENETICS; HUMAN; LOCOMOTION; METABOLISM; MUTATION; XENOPUS;

ANIMALS; BINDING SITES; BRAIN; HUMANS; HYPNOTICS AND SEDATIVES; LOCOMOTION; MALE; METHAQUALONE; MICE; MUTATION; RECEPTORS, GABA-A; STREET DRUGS; XENOPUS;

EID: 84939798277     PISSN: 0026895X     EISSN: 15210111     Source Type: Journal    
DOI: 10.1124/mol.115.099291     Document Type: Article

References (95)

1. A receptor. Mol Pharmacol 65:68-76.
2. Barcelo R (1961) A clinical study of methaqualone: a new nonbarbiturate hypnotic. Can Med Assoc J 85:1304-1305.
3. Barceloux DG (2012) Methaqualone and related compounds, in Medical Toxicology of Drug Abuse, pp 504-513, John Wiley & Sons, Inc., New York.
4. A receptors: form, pharmacology, and function. J Neurosci 29:12757-12763.
5. Belelli D, Lambert JJ, Peters JA, Wafford K, and Whiting PJ (1997) The interaction of the general anesthetic etomidate with the γ-aminobutyric acid type A receptor is influenced by a single amino acid. Proc Natl Acad Sci USA 94:11031-11036.
6. A receptors: their function in the CNS and implications for disease. Neuron 73:23-34.
7. A receptors. Br J Pharmacol 136:965-974.
8. A receptors. Br J Pharmacol 148:984-990.
9. Carroll M and Gallo G (1985) Quaaludes: The Quest for Oblivion, Chelsea House, New York.
10. A receptors. Psychopharmacology (Berl) 231:3479-3491.
11. 3H]TDBzl-etomidate, a photoreactive etomidate analogue. Biochemistry 51:836-847.
12. A) receptor. J Biol Chem 288:19343-19357.
13. Costa BM, Irvine MW, Fang G, Eaves RJ, Mayo-Martin MB, Skifter DA, Jane DE, and Monaghan DT (2010) A novel family of negative and positive allosteric modulators of NMDA receptors. J Pharmacol Exp Ther 335:614-621.
14. A receptors enhances cognition. J Pharmacol Exp Ther 316:1335-1345.
15. A receptor allosteric modulator NS16085. Biochem Pharmacol 93:370-379.
16. Desai R, Ruesch D, and Forman SA (2009) γ-amino butyric acid type A receptor mutations at β2N265 alter etomidate efficacy while preserving basal and agonist-dependent activity. Anesthesiology 111:774-784.
17. Doran A, Obach RS, Smith BJ, Hosea NA, Becker S, Callegari E, Chen C, Chen X, Choo E, and Cianfrogna J et al. (2005) The impact of P-glycoprotein on the disposition of drugs targeted for indications of the central nervous system: evaluation using the MDR1A/1B knockout mouse model. Drug Metab Dispos 33:165-174.
18. Falco M (1976) Methaqualone misuse: foreign experience and United States drug control policy. Int J Addict 11:597-610.
19. A receptor currents. Mol Pharmacol 66:988-1003.
20. A receptors. Mol Pharmacol 66:1517-1524.
21. A receptor currents. J Biol Chem 285:23614-23621.
22. Gass JT (2008) Drugs The Straight Facts: Qualuudes, Chelsea House, New York.
23. A receptor in rat brain. Biochem Pharmacol 51:1527-1534.
24. A receptors by regulating the preactivation step after GABA binding. J Neurosci 32:5707-5715.
25. Gramowski A, Jügelt K, Stüwe S, Schulze R, McGregor GP, Wartenberg-Demand A, Loock J, Schröder O, and Weiss DG (2006a) Functional screening of traditional antidepressants with primary cortical neuronal networks grown on multielectrode neurochips. Eur J Neurosci 24:455-465.
26. Gramowski A, Jügelt K, Weiss DG, and Gross GW (2004) Substance identification by quantitative characterization of oscillatory activity in murine spinal cord networks on microelectrode arrays. Eur J Neurosci 19:2815-2825.
27. Gramowski A, Stüwe S, Jügelt K, Schiffmann D, Loock J, Schröder O, Gross GW, and Weiss DG (2006b) Detecting neurotoxicity through electrical activity changes of neuronal networks on multielectrode neurochips. ALTEX 23:410-415.
28. A receptor. Neuropharmacology 35:1243-1250.
29. A receptor M1 transmembrane proline increases GABA affinity and reduces barbiturate enhancement. Neuropharmacology 42:502-521.
30. A receptors by the nonsteroidal anti-inflammatory agent, mefenamic acid. Eur J Neurosci 11:2897-2905.
31. A receptors. Pharmacol Ther 116:20-34.
32. Herzberg D (2011) Blockbusters and controlled substances: Miltown, Quaalude, and consumer demand for drugs in postwar America. Stud Hist Philos Biol Biomed Sci 42:415-426.
33. Hibbs RE and Gouaux E (2011) Principles of activation and permeation in an anion-selective Cys-loop receptor. Nature 474:54-60.
34. Hicks TP, Kaneko T, and Oka JI (1990) Receptive-field size of S1 cortical neurones is altered by methaqualone via a GABA mechanism. Can J Neurol Sci 17:30-34.
35. Hill-Venning C, Belelli D, Peters JA, and Lambert JJ (1997) Subunit-dependent interaction of the general anaesthetic etomidate with the γ-aminobutyric acid type A receptor. Br J Pharmacol 120:749-756.
36. A receptor heterogeneity: differential regional effects of a functionally selective α4β1δ/α4β3δ receptor agonist on tonic and phasic inhibition in rat brain. J Neurosci 34:16256-16272.
37. A receptor ligand Thio-4-PIOL displays distinctly different functional properties at synaptic and extrasynaptic receptors. Br J Pharmacol 170:919-932.
38. A receptors. Neuropharmacology 56:149-154.
39. A receptors through two discrete transmembrane sites. Nature 444:486-489.
40. Ionescu-Pioggia M, Bird M, Orzack MH, Benes F, Beake B, and Cole JO (1988) Methaqualone. Int Clin Psychopharmacol 3:97-109.
41. Jensen AA, Bergmann ML, Sander T, and Balle T (2010) Ginkgolide X is a potent antagonist of anionic Cys-loop receptors with a unique selectivity profile at glycine receptors. J Biol Chem 285:10141-10153.
42. A receptors. Br J Pharmacol 168:1118-1132.
43. Johnstone AF, Gross GW, Weiss DG, Schroeder OH, Gramowski A, and Shafer TJ (2010) Microelectrode arrays: a physiologically based neurotoxicity testing platform for the 21st century. Neurotoxicology 31:331-350.
44. A receptor subtypes indicate a different binding mode for GABA at these receptors. Biochem Pharmacol 84:549-557.
45. A receptors expressed in Xenopus oocytes: a mini review. Amino Acids 44:1139-1149.
46. Keov P, Sexton PM, and Christopoulos A (2011) Allosteric modulation of G protein-coupled receptors: a pharmacological perspective. Neuropharmacology 60:24-35.
47. A receptors: molecular mechanism and subunit specificity. Neuropharmacology 53:178-187.
48. Kimball AW, Burnett WT, Jr, and Doherty DG (1957) Chemical protection against ionizing radiation. I. Sampling methods for screening compounds in radiation protection studies with mice. Radiat Res 7:1-12.
49. A receptor β subunit controls a binding cavity for propofol and other alkylphenol general anesthetics. Neuropharmacology 41:952-964.
50. Lansdell SJ, Sathyaprakash C, Doward A, and Millar NS (2015) Activation of human 5-hydroxytryptamine type 3 receptors via an allosteric transmembrane site. Mol Pharmacol 87:87-95.
51. Lavé T, Coassolo P, and Reigner B (1999) Prediction of hepatic metabolic clearance based on interspecies allometric scaling techniques and in vitro-in vivo correlations. Clin Pharmacokinet 36:211-231.
52. A receptor anesthetic binding site at subunit interfaces by photolabeling with an etomidate analog. J Neurosci 26:11599-11605.
53. Löscher W and Schmidt D (1988) Which animal models should be used in the search for new antiepileptic drugs? A proposal based on experimental and clinical considerations. Epilepsy Res 2:145-181.
54. Marlo JE, Niswender CM, Days EL, Bridges TM, Xiang Y, Rodriguez AL, Shirey JK, Brady AE, Nalywajko T, and Luo Q et al. (2009) Discovery and characterization of novel allosteric potentiators of M1 muscarinic receptors reveals multiple modes of activity. Mol Pharmacol 75:577-588.
55. Mathiesen JM, Svendsen N, Bräuner-Osborne H, Thomsen C, and Ramirez MT (2003) Positive allosteric modulation of the human metabotropic glutamate receptor 4 (hmGluR4) by SIB-1893 and MPEP. Br J Pharmacol 138:1026-1030.
56. McCarthy G, Myers B, and Siegfried N (2005) Treatment for methaqualone dependence in adults. Cochrane Database Syst Rev (2):CD004146.
57. A receptors expressed in HEK cells. Neuropharmacology 56:155-160.
58. A receptors found in synaptic and extrasynaptic zones. Front Cell Neurosci 6:1-10.
59. Mozrzymas JW, Barberis A, and Cherubini E (1999a) Facilitation of miniature GABAergic currents by chlorpromazine in cultured rat hippocampal cells. Neuroreport 10:2251-2254.
60. A receptors. J Neurosci 19:2474-2488.
61. 3H] diazepam binding to rat brain synaptosomal membranes. Naunyn Schmiedebergs Arch Pharmacol 305:23-26.
62. Naik SR, Naid PR, and Sheth UK (1978) Involvement of γ-amino butyric acid (GABA) in the anticonvulsant action of methaqualone. Psychopharmacology (Berl) 57:103-107.
63. Novellino A, Scelfo B, Palosaari T, Price A, Sobanski T, Shafer TJ, Johnstone AF, Gross GW, Gramowski A, and Schroeder O et al. (2011) Development of microelectrode array based tests for neurotoxicity: assessment of interlaboratory reproducibility with neuroactive chemicals. Front Neuroeng 4:4.
64. A receptors: classification on the basis of subunit composition, pharmacology, and function. Update. Pharmacol Rev 60:243-260.
65. Parenti C, Turnaturi R, Aricò G, Gramowski-Voss A, Schroeder OH, Marrazzo A, Prezzavento O, Ronsisvalle S, Scoto GM, and Ronsisvalle G et al. (2013) The multitarget opioid ligand LP1's effects in persistent pain and in primary cell neuronal cultures. Neuropharmacology 71:70-82.
66. Parry CD, Myers B, Morojele NK, Flisher AJ, Bhana A, Donson H, and Plüddemann A (2004) Trends in adolescent alcohol and other drug use: findings from three sentinel sites in South Africa (1997-2001). J Adolesc 27:429-440.
67. Pfeiffer CC, Goldstein L, and Murphree HB (1968) Quantitative analysis of the effect of methqualone on the human EEG. J Clin Pharmacol J New Drugs 8:235-244.
68. 3H]muscimol binding in rat cerebellar and cerebral cortical membranes by picrotoxin, pentobarbitone, and etomidate. J Neurochem 41:418-425.
69. A α5 receptors by RO4938581 attenuates discrete sub-chronic and early postnatal phencyclidine (PCP)-induced cognitive deficits in rats. Psychopharmacology (Berl) 221:451-468.
70. Sanacora G and Schatzberg AF (2015) Ketamine: promising path or false prophecy in the development of novel therapeutics for mood disorders? Neuropsychopharmacology 40:259-267.
71. A/benzodiazepine receptor complex in dorsal compared to ventral rat hippocampus. Neurochem Int 52:1019-1029.
72. Sauguet L, Howard RJ, Malherbe L, Lee US, Corringer PJ, Harris RA, and Delarue M (2013) Structural basis for potentiation by alcohols and anaesthetics in a ligand-gated ion channel. Nat Commun 4:1697.
73. Saxena RC, Thacore VR, Suri ML, Agarwal TN, and Bhargava KP (1977) Electroencephalographic studies with i.v. methaqualone in man. Electroencephalogr Clin Neurophysiol 43:876-879.
74. A receptor β3 subunit involved in the actions of pentobarbital. J Physiol 524:649-676.
75. Sharma V and McNeill JH (2009) To scale or not to scale: the principles of dose extrapolation. Br J Pharmacol 157:907-921.
76. A receptors via multiple drug-binding sites. Adv Pharmacol 72:53-96.
77. A receptors. J Neurochem 80:140-148.
78. A receptors. Curr Top Med Chem 11:241-246.
79. A receptors. Eur J Pharmacol 291:99-105.
80. Stanley JL, Lincoln RJ, Brown TA, McDonald LM, Dawson GR, and Reynolds DS (2005) The mouse beam walking assay offers improved sensitivity over the mouse rotarod in determining motor coordination deficits induced by benzodiazepines. J Psychopharmacol 19:221-227.
81. A receptor gating and reduce etomidate modulation. Mol Pharmacol 74:1687-1695.
82. A) receptors. J Biol Chem 288:30373-30386.
83. Stewart DS, Pierce DW, Hotta M, Stern AT, and Forman SA (2014) Mutations at beta N265 in γ-aminobutyric acid type A receptors alter both binding affinity and efficacy of potent anesthetics. PLoS ONE 9:e111470.
84. A receptors: functional selectivity for extrasynaptic receptors is dependent on the absence of γ2. J Pharmacol Exp Ther 316:1351-1359.
85. A receptors. Br J Pharmacol 142:97-106.
86. 3 receptors: inhibition and potentiation of Cys-loop receptor signaling through a conserved transmembrane intersubunit site. J Biol Chem 287:25241-25254.
87. A receptor β subunit. Neuron 12:775-782.
88. A receptors and increase tonic currents in thalamus. Neuropharmacology 56:182-189.
89. A receptors via two distinct and separable mechanisms. Nat Neurosci 3:1274-1281.
90. Whiting PJ (2003) GABA-A receptor subtypes in the brain: a paradigm for CNS drug discovery? Drug Discov Today 8:445-450.
91. A receptors is essential for benzodiazepine agonist binding. J Biol Chem 267:1426-1429.
92. Wingrove PB, Wafford KA, Bain C, and Whiting PJ (1994) The modulatory action of loreclezole at the γ-aminobutyric acid type A receptor is determined by a single amino acid in the β2 and β3 subunit. Proc Natl Acad Sci USA 91:4569-4573.
93. A receptors. Eur J Neurosci 9:2225-2235.
94. A receptor complex. Eur J Pharmacol 300:125-130.
95. A receptors: functional and binding studies. Br J Pharmacol 121:1392-1396.