Mechanism of allosteric modulation of the cys-loop receptors

Pharmaceuticals

Volumn 3, Issue 8, 2010, Pages 2592-2609

  Chang, Yongchang ^a   Huang, Yao ^b   Whiteaker, Paul ^a  

^a BARROW NEUROLOGICAL INSTITUTE   (United States)

^b ST JOSEPH'S HOSPITAL AND MEDICAL CENTER   (United States)

Author keywords

Allosteric modulator; Cys loop receptors; Ligand gated ion channels

Indexed keywords

3ALPHA HYDROXY 5ALPHA PREGNAN 20 ONE; 4 AMINOBUTYRIC ACID A RECEPTOR; 4 ETHYL 6,7 DIMETHOXY BETA CARBOLINE 3 CARBOXYLIC ACID METHYL ESTER; 5 HYDROXYINDOLE; ALCOHOL; BUNGAROTOXIN RECEPTOR; CYSTEINE LOOP RECEPTOR; DIAZEPAM; ETOMIDATE; FLURAZEPAM; GUANINE NUCLEOTIDE BINDING PROTEIN; ION CHANNEL; MORANTEL; NICOTINIC RECEPTOR; PICROTOXIN; SEROTONIN 3A RECEPTOR; TETRAHYDRODEOXYCORTICOSTERONE; UNCLASSIFIED DRUG;

AFFINITY LABELING; ALLOSTERISM; AMINO TERMINAL SEQUENCE; BINDING AFFINITY; BINDING SITE; CHANNEL GATING; CONCENTRATION (PARAMETERS); CONCENTRATION RESPONSE; HUMAN; NEUROTRANSMISSION; NONHUMAN; PROTEIN ANALYSIS; PROTEIN FUNCTION; PROTEIN INTERACTION; PROTEIN LOCALIZATION; PROTEIN STRUCTURE; RECEPTOR DOWN REGULATION; REVIEW; SENSITIVITY ANALYSIS;

EID: 77957286146     PISSN: None     EISSN: 14248247     Source Type: Journal    
DOI: 10.3390/ph3082592     Document Type: Review

References (96)

1. Albuquerque, E.; Pereira, E.; Alkondon, M.; Rogers, S. Mammalian nicotinic acetylcholine receptors: from structure to function. Physiol. Rev. 2009, 89, 73-120.
2. Thompson, A.; Lummis, S. The 5-HT3 receptor as a therapeutic target. Expert Opin. Ther. Targets 2007, 11, 527-540.
3. Olsen, R.; Sieghart, W. International Union of Pharmacology. LXX. Subtypes of γ-aminobutyric acid (A) receptors: classification on the basis of subunit composition, pharmacology, and function. Update. Pharmacol. Rev. 2008, 60, 243-260.
4. Olsen, R.; Sieghart, W. GABAA receptors: subtypes provide diversity of function and pharmacology. Neuropharmacology 2009, 56, 273-284.
5. Johnston, G.; Chebib, M.; Hanrahan, J.; Mewett, K. GABAC receptors as drug targets. Curr. Drug Targets CNS Neurol. Disord. 2003, 2, 260.
6. Lynch, J. Native glycine receptor subtypes and their physiological roles. Neuropharmacology 2009, 56, 303-309.
7. Davies, P.; Wang, W.; Hales, T.; Kirkness, E. A novel class of ligand-gated ion channel is activated by Zn2+. J. Biol. Chem. 2003, 278, 712-717.
8. Changeux, J.; Edelstein, S. Allosteric receptors after 30 years. Neuron 1998, 21, 959-980.
9. Lester, H.; Dibas, M.; Dahan, D.; Leite, J.; Dougherty, D. Cys-loop receptors: new twists and turns. Trends. Neurosci. 2004, 27, 329-336.
10. Ortells, M.; Lunt, G. Evolutionary history of the ligand-gated ion-channel superfamily of receptors. Trends. Neurosci. 1995, 18, 121-127.
11. Bocquet, N.; Nury, H.; Baaden, M.; Poupon, C.; Changeux, J.; Delarue, M.; Corringer, P. X-ray structure of a pentameric ligand-gated ion channel in an apparently open conformation. Nature 2009, 457, 111-114.
12. Tasneem, A.; Iyer, L.M.; Jakobsson, E.; Aravind, L. Identification of the prokaryotic ligand-gated ion channels and their implications for the mechanisms and origins of animal Cys-loop ion channels. Genome. Biol. 2004, 6, R4.
13. Hilf, R.; Dutzler, R. X-ray structure of a prokaryotic pentameric ligand-gated ion channel. Nature 2008, 452, 375-379.
14. Unwin, N. Nicotinic acetylcholine receptor at 9 Å resolution. J. Mol. Biol. 1993, 229, 1101-1124.
15. Miyazawa, A.; Fujiyoshi, Y.; Unwin, N. Structure and gating mechanism of the acetylcholine receptor pore. Nature 2003, 423, 949-955.
16. Unwin, N. Refined structure of the nicotinic acetylcholine receptor at 4 Å resolution. J. Mol. Biol. 2005, 346, 967-989.
17. Celie, P.; Rossum-Fikkert, S.; Dijk, W.; Brejc, K.; Smit, A.; Sixma, T. Nicotine and carbamylcholine binding to nicotinic acetylcholine receptors as studied in AChBP crystal structures. Neuron 2004, 41, 907-914.
18. Brejc, K.; Dijk, W.; Klaassen, R.; Schuurmans, M.; Oost, J.; Smit, A.; Sixma, T. Crystal structure of an ACh-binding protein reveals the ligand-binding domain of nicotinic receptors. Nature 2001, 411, 269-276.
19. Ulens, C.; Hogg, R.; Celie, P.; Bertrand, D.; Tsetlin, V.; Smit, A.; Sixma, T. Structural determinants of selective α-conotoxin binding to a nicotinic acetylcholine receptor homolog AChBP. Proc. Natl. Acad. Sci. USA 2006, 103, 3615-3620.
20. Hansen, S.; Sulzenbacher, G.; Huxford, T.; Marchot, P.; Taylor, P.; Bourne, Y. Structures of Aplysia AChBP complexes with nicotinic agonists and antagonists reveal distinctive binding interfaces and conformations. EMBO J. 2005, 24, 3635-3646.
21. Chang, Y.; Wu, W.; Zhang, J.; Huang, Y. Allosteric activation mechanism of the cys-loop receptors. Acta Pharmacol. Sin. 2009, 30, 663-672.
22. Edelstein, S.; Changeux, J. Allosteric proteins after thirty years: the binding and state functions of the neuronal α7 nicotinic acetylcholine receptors. Experientia 1996, 52, 1083-1090.
23. Chen, Y.; Reilly, K.; Chang, Y. Evolutionarily conserved allosteric network in the cys-loop family of ligand-gated ion channels revealed by statistical covariance analyses. J. Biol. Chem. 2006, 281, 18184-18192.
24. Millar, P.; Smart, T. Binding; activation and modulation of Cys-loop receptors. Trends. Pharmacol. Sci. 2010, 31, 161-174.
25. Bartos, M.; Corradi, J.; Bouzat, C. Structural basis of activation of cys-loop receptors: the extracellular-transmembrane interface as a coupling region. Mol. Neurobiol. 2009, 40, 236-252.
26. Yakel, J. Gating of nicotinic ACh receptors: latest insights into ligand binding and function. J. Physiol. 2010, 588, 597-602.
27. Cederholm, J.; Schofield, P.; Lewis, T. Gating mechanisms in Cys-loop receptors. Eur. Biophys. J. 2009, 39, 37-49.
28. Taly, A.; Corringer, P.; Guedin, D.; Lestage, P.; Changeux, J. Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system. Nature Rev. Drug Dicovery 2009, 8, 733-750.
29. Burzomato, V.; Beato, M.; Groot-Kormelink, P.; Colquhoun, D.; Sivilotti, L. Single-channel behavior of heteromeric α1β glycine receptors: an attempt to detect a conformational change before the channel opens. J. Neurosci. 2004, 24, 10924-10940.
30. Moroni, M.; Zwart, R.; Sher, E.; Cassels, B.; Bermudez I. α4β2 nicotinic receptors with high and low acetylcholine sensitivity: pharmacology, stoichiometry, and sensitivity to long-term exposure to nicotine. Mol. Pharmacol. 2006, 70, 755-768.
31. Monod, J.; Wyman, J.; Changeux, J. On the nature of allosteric proteins: a plausible model. J. Mol. Biol. 1965, 12, 88-118.
32. Jackson, M. Spontaneous openings of the acetylcholine receptor channel. Proc. Natl. Acad. Sci. USA 1984, 81, 3901-3904.
33. Chang, Y.; Weiss, D. Allosteric activation mechanism of the α1β2γ2γ-aminobutyric acid type A receptor revealed by mutation of the conserved M2 leucine. Biophys. J. 1999, 77, 2542-2551.
34. Lape, R.; Colquhoun, D.; Sivilotti, L. On the nature of partial agonism in the nicotinic receptor superfamily. Nature 2008, 454, 722-727.
35. Campo-Soria, C.; Chang, Y.; Weiss, D. Mechanism of action of benzodiazepines on GABAA receptors. Br. J. Pharmacol. 2006, 148, 984-990.
36. Rüsch, D.; Forman, S. Classic benzodiazepines modulate the open-close equilibrium in α1β2γ2L γ-aminobutyric acid type A receptors. Anesthesiology 2005, 102, 783-792.
37. Bau, R.; Sigel, E. Benzodiazepines affect channel opening of GABAA receptors induced by either agonist binding site. Mol. Pharmacol. 2005, 67, 1005-1008.
38. Kloda, H.; Czajkowski, C. Agonist-, antagonist-, and benzodiazepine-Induced structural changes in the αMet113-Leu132 region of the GABAA receptor. Mol. Pharmacol. 2007, 71, 483-493.
39. Rüsch, D.; Zhong, H.; Forman, S. Gating allosterism at a single class of etomidate sites on α1β2γ2L GABAA receptors accounts for both direct activation and agonist modulation. J. Biol. Chem. 2004, 279, 20982-20992.
40. Li, G.; Chiara, D.; Sawyer, G.; Husain, S.; Olsen, R.; Cohen, J. Identification of a GABAA receptor anesthetic binding site at subunit interfaces by photolabeling with an etomidate analog. J. Neurosci. 2006, 26, 11599-11605.
41. Stewart, D.; Desai, R.; Cheng, Q.; Liu, A.; Forman, S. Tryptophan mutations at Azi-Etomidate photo-incorporation sites on α1 or β2 subunits enhance GABAA receptor gating and reduce etomidate modulation. Mol. Pharmacol. 2008, 74, 1687-1695.
42. Li, W.; Jin, X.; Covey, D.; Steinbach J. Neuroactive steroids and human recombinant ρ1 GABAC receptors. J. Pharmacol. Exp. Ther. 2007, 323, 236-247.
43. Li, P.; Khatri, A.; Bracamontes, J.; Weiss, D.; Steinbach, J.; Akk, G. Site-specific fluorescence reveals distinct structural changes induced in the human ρ1 GABA receptor by inhibitory neurosteroids. Mol. Pharmacol. 2010, 77, 539-546.
44. Young, G.; Zwart, R.; Walker, A.; Sher, E.; Millar N. Potentiation of α7 nicotinic acetylcholine receptors via an allosteric transmembrane site. Proc. Natl. Acad. Sci. USA 2008, 105, 14686-14691.
45. Barron, S.; McLaughlin, J.; See, J.; Richards, V.; Rosenberg, R. An allosteric modulator of α7 nicotinic receptors, N- (5-Chloro-2,4-dimethoxyphenyl)-N'- (5-methyl-3-isoxazolyl)-urea (PNU-120596), causes conformational changes in the extracellular ligand binding domain similar to those caused by acetylcholine. Mol. Pharmacol. 2009, 76, 253-263.
46. McLaughlin, J.; Barron, S.; See, J.; Rosenberg, R. Conformational changes in α7 acetylcholine receptors underlying allosteric modulation by divalent cations. BMC Pharmacol. 2009, 9, 1-13.
47. Perkins, D.; Trudell, J.; Crawford, D.; Asatryan, L.; Alkana, R.; Davies D. Loop 2 structure in glycine and GABAA receptors plays a key role in determining ethanol sensitivity. J. Biol. Chem. 2009, 284, 27304-27314.
48. Perkins, D.; JR, T.; Crawford, D.; Alkana, R.; Davies, D. Targets for ethanol action and antagonism in loop 2 of the extracellular domain of glycine receptors. J. Neurochem. 2008, 106, 1337-1349.
49. Yevenes, G.; Moraga-Cid, G.; Peoples, R.; Schmalzing, G.; Aguayo, L. A selective Gβγ-linked intracellular mechanism for modulation of a ligand-gated ion channel by ethanol. Proc. Natl. Acad. Sci. USA 2008, 51, 20523-20528.
50. Chang, Y.; Weiss, D. Site-specific fluorescence reveals distinct structural changes with GABA receptor activation and antagonism. Nat. Neurosci. 2002, 5, 1163-1168.
51. Zhang, J.; Xue, F.; Chang, Y. Agonist- and antagonist-induced conformational changes of loop F and their contributions to the ρ GABA receptor function. J. Physiol. 2009, 587, 139-153.
52. Chang, C.; Olcese, R.; Olsen, R. A single M1 residue in the β2 subunit alters channel gating of GABAA receptor in anesthetic modulation and direct activation. J. Biol. Chem. 2003, 278, 42821-42828.
53. Hu, X.; Peoples, R. Arginine 246 of the pretransmembrane domain 1 region alters 2,2,2-richloroethanol action in the 5-hydroxytryptamine3A receptor. J. Pharmacol. Exp. Ther. 2008, 324, 1011-1018.
54. Hosie, A.; Dunne, E.; Harvey, R.; Smart, T. Zinc-mediated inhibition of GABA (A) receptors: discrete binding sites underlie subtype specificity. Nat. Neurosci. 2003, 6, 362-369.
55. Kash, T.; Jenkins, A.; Kelley, J.; Trudell, J.; Harrison, N. Coupling of agonist binding to channel gating in the GABAA receptor. Nature 2003, 421, 272-275.
56. Kash, T.; Dizon, M.; Trudell, J.; Harrison, N. Charged residues in the β2 subunit involved in GABAA receptor activation. J. Biol. Chem. 2004, 279, 4887-4893.
57. Duncalfe, L.; Carpenter, M.; Smillie, L.; Martin, I.; Dunn, S. The major site of photoaffinity labeling of the GABAA receptor by [3H] flunitrazepam is histidine 102 of the a subunit. J. Biol. Chem. 1996, 271, 9209-9214.
58. Wieland, H.; Luddens, H.; Seeburg, P. A single histidine in GABAA receptors is essential for benzodiazepine agonist binding. J. Biol. Chem. 1992, 267, 1426-1429.
59. Amin, J.; Brooks-Kayal, A.; Weiss, D. Two tyrosine residues on the a subunit are crucial for benzodiazepine binding and allosteric modulation of γ-aminobutyric acid A receptors. Mol. Pharmacol. 1997, 51, 833-841.
60. Schaerer, M.; Buhr, A.; Baur, R.; Sigel, E. Amino acid residue 200 on the α subunit of GABA (A) receptors affects the interaction with selected benzodiazepine binding site ligands. Eur. J. Pharmacol. 1998, 354, 283-288.
61. Buhr, A.; Schaerer, M.; Baur, R.; Sigel, E. Residues at positions 206 and 209 of the α subunit of γ-aminobutyric acid A receptors influence affinities for benzodiazepine binding site ligands. Mol. Pharmacol. 1997, 52, 676-682.
62. Buhr, A.; Baur, R.; Sigel, E. Subtle changes in residue 77 of the γ subunit of α1β2γ2 GABAA receptors drastically alter the affinity for ligands of the benzodiazepine binding site and suggest the presence of two sites. J. Biol. Chem. 1997, 272, 11799-11804.
63. Wingrove, P.; Thompson, S.; Wafford, K.; Whiting, P. Key amino acids in the gamma subunit of the γ-aminobutyric acid A receptor that determine ligand binding and modulation at the benzodiazepine site. Mol. Pharmacol. 1997, 52, 874-881.
64. Kucken, A.M.; Teissere, J.A.; Seffinga-Clark, J.; Wagner, D.A.; Czajkowski, C. Structural requirements for imidazobenzodiazepine binding to GABA (A) receptors. Mol. Pharmacol. 2003, 63, 289-296.
65. Teissere, J.; Czajkowski, C. A β-strand in the γ2 subunit lines the benzodiazepine binding site of the GABAA receptor: structural rearrangements detected during channel gating. J. Neurosci. 2001, 21, 4977-4986.
66. Buhr, A.; Sigel, E. A point mutation in the γ2 subunit of γ-aminobutyric acid type A receptors results in altered benzodiazepine site specificity. Proc. Natl. Acad. Sci. USA 1997, 94, 8824-8829.
67. Sancar, F.; Ericksen, S.; Kucken, A.; Teissére, J.; Czajkowski, C. Structural determinants for high-affinity zolpidem binding to GABA-A receptors. Mol. Pharmacol. 2007, 71, 38-46.
68. Seo, S.; Henry, J.; Lewis, A.; Wang, N.; Levandoski, M. The positive allosteric modulator morantel binds at noncanonical subunit interfaces of neuronal nicotinic acetylcholine receptors. J. Neurosci. 2009, 29, 8734-8742.
69. Jenkins, A.; Greenblatt, E.; Faulkner, H.; Bertaccini, E.; Light A.; Lin, A.; Andreasen, A.; Viner, A.; Trudell, J.; Harrison, N. Evidence for a common binding cavity for three general anesthetics within the GABAA receptor. J. Neurosci. 2001, 21, RC136.
70. Wick, M.; Mihic, S.; Ueno, S.; Mascia, M.; Trudell, J.; Brozowski, S.; Ye, Q.; Harrison, N.; Harris, R. Mutations of gamma-aminobutyric acid and glycine receptors change alcohol cutoff: evidence for an alcohol receptor? Proc. Natl. Acad. Sci. USA 1998, 95, 6504-6509.
71. Frank, N. General anaesthesia: from molecular targets to neuronal pathways of sleep and arousal. Nat. Rev. Neurosci. 2008, 9, 370-386.
72. Belelli, D.; Lambert, J.; Peters, J.; Wafford, K.; Whiting, P. 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 1997, 94, 11031-11036.
73. Bali, M.; Akabas, M. Defining the propofol binding site location on the GABAA receptor. Mol. Pharmacol. 2004, 65, 68-76.
74. Lopreato, G.; Banerjee, P.; Mihic, S. Amino acids in transmembrane domain two influence anesthetic enhancement of serotonin-3A receptor function. Brain Res. Mol. Brain Res. 2003, 118, 45-51.
75. Li, G.; Chiara, D.; Cohen, J.; Olsen, R. Numerous classes of general anesthetics inhibit etomidate binding to γ-aminobutyric acid type A (GABAA) receptors. J. Biol. Chem. 2010, 285, 8615-8620.
76. Li, G.; Chiara, D.; Cohen, J.; RW, O. Neurosteroids allosterically modulate binding of the anesthetic etomidate to γ-aminobutyric acid type A receptors. J. Biol. Chem. 2009, 284, 11771-11775.
77. Belelli, D.; Lambert, J. Neurosteroids: endogenous regulators of the GABAA receptor. Nat. Rev. Neurosci. 2005, 6, 565-575.
78. Hosie, A.; Wilkins, M.; da Silva, H.; Smart, T. Endogenous neurosteroids regulate GABAA receptors through two discrete transmembrane sites. Nature 2006, 444, 486-489.
79. Krause, R.; Buisson, B.; Bertrand, S.; Corringer, P.; Galzi, J.; Changeux, J.; Bertrand, D. Ivermectin: a positive allosteric effector of the α7 neuronal nicotinic acetylcholine receptor. Mol. Pharmacol. 1998, 53, 283-294.
80. Zwart, R.; De Filippi, G.; Broad, L.; McPhie, G.; Pearson, K.; Baldwinson, T.; Sher, E. 5-Hydroxyindole potentiates human α7 nicotinic receptor-mediated responses and enhances acetylcholine-induced glutamate release in cerebellar slices. Neuropharmacology 2002, 43, 374-384.
81. Charpantier, E.; Wiesner, A.; Huh, K.; Ogier, R.; Hoda, J.; Allaman, G.; Raggenbass, M.; Feuerbach, D.; Bertrand, D.; Fuhrer, C. α7 neuronal nicotinic acetylcholine receptors are negatively regulated by tyrosine phosphorylation and Src-family kinases. J. Neurosci. 2005, 25, 9836-9849.
82. Ng, H.; Whittemore, E.; Tran, M.; Hogenkamp, D.; Broide, R.; Johnstone, T.; Zheng, L.; Stevens, K.; Gee, K. Nootropic α7 nicotinic receptor allosteric modulator derived from GABAA receptor modulators. Proc. Natl. Acad. Sci. USA 2007, 104, 8059-8064.
83. Timmermann, D.; Grønlien, J.; Kohlhaas, K.; Nielsen, E.; Dam, E.; Jørgensen, T.; Ahring, P.; Peters, D.; Holst, D.; Christensen, J.; Malysz, J.; Briggs, C.; Gopalakrishnan, M.; Olsen, G. An allosteric modulator of the α7 nicotinic acetylcholine receptor possessing cognition-enhancing properties in vivo. J. Pharmacol. Exp. Ther. 2007, 323, 294-307.
84. Hu, X.; Lovinger, D. The L293 residue in transmembrane domain 2 of the 5-HT3A receptor is a molecular determinant of allosteric modulation by 5-hydroxyindole. Neuropharmacology 2008, 54, 1153-1165.
85. Hurst, R.; Hajós, M.; Raggenbass, M.; Wall, T.; Higdon, N.; Lawson, J.; Rutherford-Root, K.; Berkenpas, M.; Hoffmann, W.; Piotrowski, D.; Groppi, V.; Allaman, G.; Ogier, R.; Bertrand, S.; Bertrand, D.; Arneric, S. A novel positive allosteric modulator of the α7 neuronal nicotinic acetylcholine receptor: in vitro and in vivo characterization. J. Neurosci. 2005, 25, 4396-4405.
86. Smart, T.; Moss, S.; Xie, X.; Huganir, R. GABAA receptors are differentially sensitive to zinc: dependence on subunit composition. Br. J. Pharmacol. 1991, 103, 1837-1839.
87. Chang, Y.; Amin, J.; Weiss, D. Zinc is a mixed antagonist of homomeric ρ γ-aminobutyric acid-activated channels. Mol. Pharmacol. 1995, 47, 595-602.
88. Guo, X.; Lester, R. Regulation of nicotinic acetylcholine receptor desensitization by Ca2+. J. Neurophysiol. 2007, 97, 93-101.
89. Chimienti, F.; Hogg, R.; Plantard, L.; Lehmann, C.; Brakch, N.; Fischer, J.; Huber, M.; Bertrand, D.; Hohl, D. Identification of SLURP-1 as an epidermal neuromodulator explains the clinical phenotype of Mal de Meleda. Hum. Mol. Genet. 2003, 12, 3017-3024.
90. Tipps, M.; Lawshe, J.; Ellington, A.; Mihic, S. Identification of novel specific allosteric modulators of the glycine receptor using phage display. J. Biol. Chem. 2010, Epub ahead of print.
91. Trudell, J.; Yue, M.; Bertaccini, E.; Jenkins, A.; Harrison, N. Molecular modeling and mutagenesis reveals a tetradentate binding site for Zn2+ in GABA (A) αβ receptors and provides a structural basis for the modulating effect of the gamma subunit. J. Chem. Inf. Mod. 2008, 48, 344-349.
92. Le Novère N., Grutter T.; Changeux J. Models of the extracellular domain of the nicotinic receptors and of agonist- and Ca2+-binding sites. Proc Natl Acad Sci USA 2002, 99, 3210-3215.
93. Galzi J., Bertrand S., Corringer P., Changeux J., Bertrand D. Identification of calcium binding sites that regulate potentiation of a neuronal nicotinic acetylcholine receptor. EMBO J 1996, 15, 5824-5832.
94. Yevenes, G.; Moraga-Cid, G.; Guzmán, L.; Haeger, S.; Oliveira, L.; Olate, J.; Schmalzing, G.; Aguayo, L. Molecular determinants for G protein βγ modulation of ionotropic glycine receptors. J. Biol. Chem. 2006, 281, 39300-39307.
95. Atack, J. Preclinical and clinical pharmacology of the GABAA receptor α5 subtype-selective inverse agonist alpha5IA. Pharmacol. Ther. 2010, 125, 11-26.
96. Ballard, T.; Knoflach, F.; Prinssen, E.; Borroni, E.; Vivian, J.; Basile, J.; Gasser, R.; Moreau, J.; Wettstein, J.; Buettelmann, B.; Knust, H.; Thomas, A.; Trube, G.; Hernandez, M. RO4938581, a novel cognitive enhancer acting at GABAA α5 subunit-containing receptors. Psychopharmocology (Berlin) 2009, 202, 207-223.