Profiling 976 ToxCast chemicals across 331 enzymatic and receptor signaling assays

Chemical Research in Toxicology

Volumn 26, Issue 6, 2013, Pages 878-895

  Sipes, Nisha S ^a   Martin, Matthew T ^a   Kothiya, Parth ^a   Reif, David M ^a   Judson, Richard S ^a   Richard, Ann M ^a   Houck, Keith A ^a   Dix, David J ^a   Kavlock, Robert J ^a   Knudsen, Thomas B ^a  

^a U S ENVIRONMENTAL PROTECTION AGENCY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

CYTOCHROME P450 2C19; CYTOCHROME P450 2C9; DITHIOCARBAMIC ACID; DOPAMINE; DRUG; FOOD ADDITIVE; FUNGICIDE; G PROTEIN COUPLED RECEPTOR; HEAVY METAL; MITOCHONDRIAL PROTEIN; NORADRENALIN; PESTICIDE; PLASTICIZER; SURFACTANT; CARRIER PROTEIN; ENZYME; ORGANIC COMPOUND;

ARTICLE; BIOLOGICAL ACTIVITY; CHEMICAL ANALYSIS; CHEMICAL INTERACTION; CHEMICAL STRUCTURE; CONTROLLED STUDY; ENZYMATIC ASSAY; HALF MAXIMAL ACTIVITY CONCENTRATION; HIGH THROUGHPUT SCREENING; HUMAN; LIGAND BINDING; NONHUMAN; PARAMETERS; TOXICOLOGY; ANIMAL; ANTAGONISTS AND INHIBITORS; DRUG EFFECTS; GUINEA PIG; METABOLISM; RAT; SIGNAL TRANSDUCTION; TOXICITY;

ANIMALS; ENZYMES; GUINEA PIGS; HIGH-THROUGHPUT SCREENING ASSAYS; HUMANS; MEMBRANE TRANSPORT PROTEINS; ORGANIC CHEMICALS; RATS; RECEPTORS, G-PROTEIN-COUPLED; SIGNAL TRANSDUCTION;

EID: 84879179678     PISSN: 0893228X     EISSN: 15205010     Source Type: Journal    
DOI: 10.1021/tx400021f     Document Type: Article

References (95)

1. NRC (2007) Toxicity Testing in the 21st Century: A Vision and a Strategy, National Academies Press, Washington, D.C.
2. Kavlock, R., Chandler, K., Houck, K., Hunter, S., Judson, R., Kleinstreuer, N., Knudsen, T., Martin, M., Padilla, S., Reif, D., Richard, A., Rotroff, D., Sipes, N., and Dix, D. (2012) Update on EPA's ToxCast program: providing high throughput decision support tools for chemical risk management Chem. Res. Toxicol. 25, 1287-1302
3. Judson, R. S., Houck, K. A., Kavlock, R. J., Knudsen, T. B., Martin, M. T., Mortensen, H. M., Reif, D. M., Rotroff, D. M., Shah, I., Richard, A. M., and Dix, D. J. (2010) In vitro screening of environmental chemicals for targeted testing prioritization: the ToxCast project Environ. Health Perspect. 118, 485-492
4. NRC (1984) Toxicity Testing: Strategies to Determine Needs and Priorities, National Academies Press, Washington, D.C.
5. Keiser, M. J., Setola, V., Irwin, J. J., Laggner, C., Abbas, A. I., Hufeisen, S. J., Jensen, N. H., Kuijer, M. B., Matos, R. C., Tran, T. B., Whaley, R., Glennon, R. A., Hert, J., Thomas, K. L., Edwards, D. D., Shoichet, B. K., and Roth, B. L. (2009) Predicting new molecular targets for known drugs Nature 462, 175-181
6. Xie, L., Xie, L., and Bourne, P. E. (2011) Structure-based systems biology for analyzing off-target binding Curr. Opin. Struct. Biol. 21, 189-199
7. Ankley, G. T., Bennett, R. S., Erickson, R. J., Hoff, D. J., Hornung, M. W., Johnson, R. D., Mount, D. R., Nichols, J. W., Russom, C. L., Schmieder, P. K., Serrrano, J. A., Tietge, J. E., and Villeneuve, D. L. (2010) Adverse outcome pathways: a conceptual framework to support ecotoxicology research and risk assessment Environ. Toxicol. Chem. 29, 730-741
8. Martin, M. T., Dix, D. J., Judson, R. S., Kavlock, R. J., Reif, D. M., Richard, A. M., Rotroff, D. M., Romanov, S., Medvedev, A., Poltoratskaya, N., Gambarian, M., Moeser, M., Makarov, S. S., and Houck, K. A. (2010) Impact of environmental chemicals on key transcription regulators and correlation to toxicity end points within EPA's ToxCast program Chem. Res. Toxicol. 23, 578-590
9. Knudsen, T. B., Houck, K. A., Sipes, N. S., Singh, A. V., Judson, R. S., Martin, M. T., Weissman, A., Kleinstreuer, N. C., Mortensen, H. M., Reif, D. M., Rabinowitz, J. R., Setzer, R. W., Richard, A. M., Dix, D. J., and Kavlock, R. J. (2011) Activity profiles of 309 ToxCast chemicals evaluated across 292 biochemical targets Toxicology 282, 1-15
10. Berg, E. L., Kunkel, E. J., Hytopoulos, E., and Plavec, I. (2006) Characterization of compound mechanisms and secondary activities by BioMAP analysis J. Pharmacol. Toxicol. Methods 53, 67-74
11. Giuliano, K. A., Johnston, P. A., Gough, A., and Taylor, D. L. (2006) Systems cell biology based on high-content screening Methods Enzymol. 414, 601-619
12. Rotroff, D. M., Beam, A. L., Dix, D. J., Farmer, A., Freeman, K. M., Houck, K. A., Judson, R. S., LeCluyse, E. L., Martin, M. T., Reif, D. M., and Ferguson, S. S. (2010) Xenobiotic-metabolizing enzyme and transporter gene expression in primary cultures of human hepatocytes modulated by ToxCast chemicals J. Toxicol. Environ. Health, Part B 13, 329-346
13. Chandler, K. J., Barrier, M., Jeffay, S., Nichols, H. P., Kleinstreuer, N. C., Singh, A. V., Reif, D. M., Sipes, N. S., Judson, R. S., Dix, D. J., Kavlock, R., Hunter, E. S., III, and Knudsen, T. B. (2011) Evaluation of 309 environmental chemicals using a mouse embryonic stem cell adherent cell differentiation and cytotoxicity assay PLoS One 6, e18540
14. Huang, R., Xia, M., Cho, M. H., Sakamuru, S., Shinn, P., Houck, K. A., Dix, D. J., Judson, R. S., Witt, K. L., Kavlock, R. J., Tice, R. R., and Austin, C. P. (2011) Chemical genomics profiling of environmental chemical modulation of human nuclear receptors Environ. Health Perspect. 119, 1142-1148
15. Inglese, J., Auld, D. S., Jadhav, A., Johnson, R. L., Simeonov, A., Yasgar, A., Zheng, W., and Austin, C. P. (2006) Quantitative high-throughput screening: a titration-based approach that efficiently identifies biological activities in large chemical libraries Proc. Natl. Acad. Sci. U.S.A. 103, 11473-11478
16. Shukla, S. J., Huang, R., Austin, C. P., and Xia, M. (2010) The future of toxicity testing: a focus on in vitro methods using a quantitative high-throughput screening platform Drug Discovery Today 15, 997-1007
17. Collins, F. S., Gray, G. M., and Bucher, J. R. (2008) Toxicology. Transforming environmental health protection Science 319, 906-907
18. Worth, A. P., Lapenna, S., and Serafimova, R. (2013) QSAR and metabolic assessment tools in the assessment of genotoxicity Methods Mol. Biol. 930, 125-162
19. Judson, R. S., Martin, M. T., Egeghy, P., Gangwal, S., Reif, D. M., Kothiya, P., Wolf, M., Cathey, T., Transue, T., Smith, D., Vail, J., Frame, A., Mosher, S., Cohen Hubal, E. A., and Richard, A. M. (2012) Aggregating data for computational toxicology applications: The U.S. Environmental Protection Agency (EPA) Aggregated Computational Toxicology Resource (ACToR) System Int. J. Mol. Sci. 13, 1805-1831
20. Ihaka, R. and Gentleman, R. (1996) R: A Language for Data Analysis and Graphics J. Comp. Graph. Stat. 5, 299-314
21. R Development Core Team (2012) R: A Language and Environment for Statistical Computing, ISBN 3-900051-07-0, R Foundation for Statistical Computing, Vienna, Austria, http://www.R-project.org.
22. O'Boyle, N. M., Banck, M., James, C. A., Morley, C., Vandermeersch, T., and Hutchison, G. R. (2011) Open Babel: An open chemical toolbox J. Cheminform. 3, 33
23. Yap, C. W. (2011) PaDEL-descriptor: an open source software to calculate molecular descriptors and fingerprints J. Comput. Chem. 32, 1466-1474
24. Cline, M. S., Smoot, M., Cerami, E., Kuchinsky, A., Landys, N., Workman, C., Christmas, R., Avila-Campilo, I., Creech, M., Gross, B., Hanspers, K., Isserlin, R., Kelley, R., Killcoyne, S., Lotia, S., Maere, S., Morris, J., Ono, K., Pavlovic, V., Pico, A. R., Vailaya, A., Wang, P. L., Adler, A., Conklin, B. R., Hood, L., Kuiper, M., Sander, C., Schmulevich, I., Schwikowski, B., Warner, G. J., Ideker, T., and Bader, G. D. (2007) Integration of biological networks and gene expression data using Cytoscape Nat. Protoc. 2, 2366-2382
25. Schmidt, C. J., Fadayel, G. M., Sullivan, C. K., and Taylor, V. L. (1992) 5-HT2 receptors exert a state-dependent regulation of dopaminergic function: studies with MDL 100,907 and the amphetamine analogue, 3,4- methylenedioxymethamphetamine Eur. J. Pharmacol. 223, 65-74
26. Jiaravuthisan, M. M., Sasseville, D., Vender, R. B., Murphy, F., and Muhn, C. Y. (2007) Psoriasis of the nail: anatomy, pathology, clinical presentation, and a review of the literature on therapy J. Am. Acad. Dermatol. 57, 1-27
27. Jensen, K., Johnson, L. A., Jacobson, P. A., Kachler, S., Kirstein, M. N., Lamba, J., and Klotz, K. N. (2012) Cytotoxic purine nucleoside analogues bind to A1, A2A, and A3 adenosine receptors Naunyn-Schmiedeberg's Arch. Pharmacol. 385, 519-525
28. Witorsch, R. J. and Thomas, J. A. (2010) Personal care products and endocrine disruption: A critical review of the literature Crit. Rev. Toxicol. 40 (Suppl 3) 1-30
29. Tickner, J. A., Schettler, T., Guidotti, T., McCally, M., and Rossi, M. (2001) Health risks posed by use of Di-2-ethylhexyl phthalate (DEHP) in PVC medical devices: a critical review Am. J. Ind. Med. 39, 100-111
30. U.S. Consumer Product Safety Commission by Versar, Inc. and Syracuse Research Corporation (SRC) (2010) Review of exposure and toxicity data for phthalate substitutes, www.cpsc.gov/about/cpsia/phthalsub.pdf (accessed Jan 4, 2012).
31. Blair, R. M., Fang, H., Branham, W. S., Hass, B. S., Dial, S. L., Moland, C. L., Tong, W., Shi, L., Perkins, R., and Sheehan, D. M. (2000) The estrogen receptor relative binding affinities of 188 natural and xenochemicals: structural diversity of ligands Toxicol. Sci. 54, 138-153
32. Dubois, K. P., Raymund, A. B., and Hietbrink, B. E. (1961) Inhibitory action of dithiocarbamates on enzymes of animal tissues Toxicol. Appl. Pharmacol. 3, 236-255
33. Miller, D. B. (1982) Neurotoxicity of the pesticidal carbamates Neurobehav. Toxicol. Teratol. 4, 779-787
34. O'Carroll, R. E., Masterton, G., Dougall, N., Ebmeier, K. P., and Goodwin, G. M. (1995) The neuropsychiatric sequelae of mercury poisoning. The Mad Hatter's disease revisited Br. J. Psychiatry 167, 95-98
35. Harada, M. (1995) Minamata disease: methylmercury poisoning in Japan caused by environmental pollution Crit. Rev. Toxicol. 25, 1-24
36. Haroon, M. and Fitzgerald, O. (2012) Pathogenetic overview of psoriatic disease J. Rheumatol., Suppl. 89, 7-10
37. Chen, X., Beutler, J. A., McCloud, T. G., Loehfelm, A., Yang, L., Dong, H. F., Chertov, O. Y., Salcedo, R., Oppenheim, J. J., and Howard, O. M. (2003) Tannic acid is an inhibitor of CXCL12 (SDF-1alpha)/CXCR4 with antiangiogenic activity Clin. Cancer Res. 9, 3115-3123
38. Di Gennaro, A. and Haeggstrom, J. Z. (2012) The leukotrienes: immune-modulating lipid mediators of disease Adv. Immunol. 116, 51-92
39. Keil, D. E., Mehlmann, T., Butterworth, L., and Peden-Adams, M. M. (2008) Gestational exposure to perfluorooctane sulfonate suppresses immune function in B6C3F1 mice Toxicol. Sci. 103, 77-85
40. Lounkine, E., Keiser, M. J., Whitebread, S., Mikhailov, D., Hamon, J., Jenkins, J. L., Lavan, P., Weber, E., Doak, A. K., Cote, S., Shoichet, B. K., and Urban, L. (2012) Large-scale prediction and testing of drug activity on side-effect targets Nature 486, 361-367
41. Paolini, G. V., Shapland, R. H., van Hoorn, W. P., Mason, J. S., and Hopkins, A. L. (2006) Global mapping of pharmacological space Nat. Biotechnol. 24, 805-815
42. Duax, W. L., Griffin, J. F., Weeks, C. M., and Wawrzak, Z. (1988) The mechanism of action of steroid antagonists: insights from crystallographic studies J. Steroid Biochem. 31, 481-492
43. Tabira, Y., Nakai, M., Asai, D., Yakabe, Y., Tahara, Y., Shinmyozu, T., Noguchi, M., Takatsuki, M., and Shimohigashi, Y. (1999) Structural requirements of para-alkylphenols to bind to estrogen receptor Eur. J. Biochem. 262, 240-245
44. Reigart, J. R. and Roberts, J. R. (1999) N-Methyl Carbamate Insecticides, in Recognition and Management of Pesticide Poisoning (Langner, G., Ed.) pp 48-54, U.S. Environmental Protection Agency, Washington, D.C.
45. Vilches-Herrera, M., Miranda-Sepulveda, J., Rebolledo-Fuentes, M., Fierro, A., Luhr, S., Iturriaga-Vasquez, P., Cassels, B. K., and Reyes-Parada, M. (2009) Naphthylisopropylamine and N-benzylamphetamine derivatives as monoamine oxidase inhibitors Bioorg. Med. Chem. 17, 2452-2460
46. Sipes, N. S., Martin, M. T., Reif, D. M., Kleinstreuer, N. C., Judson, R. S., Singh, A. V., Chandler, K. J., Dix, D. J., Kavlock, R. J., and Knudsen, T. B. (2011) Predictive models of prenatal developmental toxicity from ToxCast high-throughput screening data Toxicol. Sci. 124, 109-127
47. Martin, M. T., Knudsen, T. B., Reif, D. M., Houck, K. A., Judson, R. S., Kavlock, R. J., and Dix, D. J. (2011) Predictive model of rat reproductive toxicity from ToxCast high throughput screening Biol. Reprod. 85, 327-339
48. Oishi, K., Toyao, K., and Kawano, Y. (2008) Suppression of estrogenic activity of 17-beta-estradiol by beta-cyclodextrin Chemosphere 73, 1788-1792
49. Del Valle, E. M. M. (2004) Cyclodextrins and their uses: a review Process Biochem. (Oxford, U. K.) 39, 1033-1046
50. Wetmore, B. A., Wambaugh, J. F., Ferguson, S. S., Sochaski, M. A., Rotroff, D. M., Freeman, K., Clewell, H. J., III, Dix, D. J., Andersen, M. E., Houck, K. A., Allen, B., Judson, R. S., Singh, R., Kavlock, R. J., Richard, A. M., and Thomas, R. S. (2012) Integration of dosimetry, exposure, and high-throughput screening data in chemical toxicity assessment Toxicol. Sci. 125, 157-174
51. Dix, D. J., Houck, K. A., Judson, R. S., Kleinstreuer, N. C., Knudsen, T. B., Martin, M. T., Reif, D. M., Richard, A. M., Shah, I., Sipes, N. S., and Kavlock, R. J. (2012) Incorporating biological, chemical, and toxicological knowledge into predictive models of toxicity Toxicol. Sci. 130, 440-441
52. Knudsen, T. B. and Kleinstreuer, N. C. (2011) Disruption of embryonic vascular development in predictive toxicology Birth Defects Res., Part C 93, 312-323
53. Kleinstreuer, N., Dix, D., Rountree, M., Baker, N., Sipes, N., Reif, D., Spencer, R., and Knudsen, T. (2013) A computational model predicting disruption of blood vessel development PLoS Comput. Biol. 9, e1002996
54. Kleinstreuer, N. C. and Knudsen, T. B. (2011) Predictive Modeling and Computational Toxicology, in Developmental and Reproductive Toxicology: A Practical Approach (Hood, R. D., Ed.) pp 578-591, Informa Healthcare Books, London, U.K.
55. Hals, P. A., Hall, H., and Dahl, S. G. (1988) Muscarinic cholinergic and histamine H1 receptor binding of phenothiazine drug metabolites Life Sci. 43, 405-412
56. Huerta-Bahena, J., Villalobos-Molina, R., and Garcia-Sainz, J. A. (1983) Trifluoperazine and chlorpromazine antagonize alpha 1-but not alpha2-adrenergic effects Mol. Pharmacol. 23, 67-70
57. Trichard, C., Paillere-Martinot, M. L., Attar-Levy, D., Recassens, C., Monnet, F., and Martinot, J. L. (1998) Binding of antipsychotic drugs to cortical 5-HT2A receptors: a PET study of chlorpromazine, clozapine, and amisulpride in schizophrenic patients Am. J. Psychiatry 155, 505-508
58. York, D. H. (1972) Dopamine receptor blockade -a central action of chlorpromazine on striatal neurones Brain Res. 37, 91-99
59. Arnt, J. and Skarsfeldt, T. (1998) Do novel antipsychotics have similar pharmacological characteristics? A review of the evidence Neuropsychopharmacology 18, 63-101
60. Tam, S. W. and Cook, L. (1984) Sigma opiates and certain antipsychotic drugs mutually inhibit (+)-[3H] SKF 10,047 and [3H]haloperidol binding in guinea pig brain membranes Proc. Natl. Acad. Sci. U.S.A. 81, 5618-5621
61. Tuppurainen, H., Kuikka, J. T., Viinamaki, H., Husso, M., and Tiihonen, J. (2009) Dopamine D2/3 receptor binding potential and occupancy in midbrain and temporal cortex by haloperidol, olanzapine and clozapine Psychiatry Clin. Neurosci. 63, 529-537
62. McCort, G., Hoornaert, C., Aletru, M., Denys, C., Duclos, O., Cadilhac, C., Guilpain, E., Dellac, G., Janiak, P., Galzin, A. M., Delahaye, M., Guilbert, F., and O'Connor, S. (2001) Synthesis and SAR of 3-and 4-substituted quinolin-2-ones: discovery of mixed 5-HT(1B)/5-HT(2A) receptor antagonists Bioorg. Med. Chem. 9, 2129-2137
63. LaFrate, A. L., Carlson, K. E., and Katzenellenbogen, J. A. (2009) Steroidal bivalent ligands for the estrogen receptor: design, synthesis, characterization and binding affinities Bioorg. Med. Chem. 17, 3528-3535
64. Yeh, S., Miyamoto, H., Shima, H., and Chang, C. (1998) From estrogen to androgen receptor: a new pathway for sex hormones in prostate Proc. Natl. Acad. Sci. U.S.A. 95, 5527-5532
65. Rider, C. V., Hartig, P. C., Cardon, M. C., and Wilson, V. S. (2009) Comparison of chemical binding to recombinant fathead minnow and human estrogen receptors alpha in whole cell and cell-free binding assays Environ. Toxicol. Chem. 28, 2175-2181
66. Planting, A., van der Gaast, A., Schoffski, P., Bartkowski, M., Verheij, C., Noe, D., Ferrante, K., and Verweij, J. (2005) A phase I and pharmacologic study of the matrix metalloproteinase inhibitor CP-471,358 in patients with advanced solid tumors Cancer Chemother. Pharmacol. 55, 136-142
67. Dalvie, D., Cosker, T., Boyden, T., Zhou, S., Schroeder, C., and Potchoiba, M. J. (2008) Metabolism distribution and excretion of a matrix metalloproteinase-13 inhibitor, 4-[4-(4-fluorophenoxy)-benzenesulfonylamino] tetrahydropyran-4-carboxylic acid hydroxyamide (CP-544439), in rats and dogs: assessment of the metabolic profile of CP-544439 in plasma and urine of humans Drug Metab. Dispos. 36, 1869-1883
68. Shiau, A. K., Barstad, D., Loria, P. M., Cheng, L., Kushner, P. J., Agard, D. A., and Greene, G. L. (1998) The structural basis of estrogen receptor/coactivator recognition and the antagonism of this interaction by tamoxifen Cell 95, 927-937
69. Gaido, K. W., Leonard, L. S., Maness, S. C., Hall, J. M., McDonnell, D. P., Saville, B., and Safe, S. (1999) Differential interaction of the methoxychlor metabolite 2,2-bis-(p-hydroxyphenyl)-1,1,1-trichloroethane with estrogen receptors alpha and beta Endocrinology 140, 5746-5753
70. Watson, N., Reddy, H., Stefanich, E., and Eglen, R. M. (1995) Characterization of the interaction of zamifenacin at muscarinic receptors in vitro Eur. J. Pharmacol. 285, 135-142
71. Watson, N., Daniels, D. V., Ford, A. P., Eglen, R. M., and Hegde, S. S. (1999) Comparative pharmacology of recombinant human M3 and M5 muscarinic receptors expressed in CHO-K1 cells Br. J. Pharmacol. 127, 590-596
72. Pasternak, G. W., Snowman, A. M., and Snyder, S. H. (1975) Selective enhancement of [3H]opiate agonist binding by divalent cations Mol. Pharmacol. 11, 735-744
73. Williams, S. P. and Sigler, P. B. (1998) Atomic structure of progesterone complexed with its receptor Nature 393, 392-396
74. Emonds-Alt, X., Advenier, C., Cognon, C., Croci, T., Daoui, S., Ducoux, J. P., Landi, M., Naline, E., Neliat, G., Poncelet, M., Proietto, V., Van Broeck, D., Vilain, P., Soubrie, P., Le Fur, G., Maffrand, J. P., and Breliere, J. C. (1997) Biochemical and pharmacological activities of SR 144190, a new potent non-peptide tachykinin NK2 receptor antagonist Neuropeptides 31, 449-458
75. Ishizaki, H., Yamada, S., Yanagiguchi, K., Koyama, Z., Ikeda, T., and Hayashi, Y. (2009) Pre-treatment with tannic acid inhibits the intracellular IL-8 production by chitosan in a human oral epithelial cancer cell line Oral Med. Pathol. 13, 135-141
76. Amitai, G., Moorad, D., Adani, R., and Doctor, B. P. (1998) Inhibition of acetylcholinesterase and butyrylcholinesterase by chlorpyrifos-oxon Biochem. Pharmacol. 56, 293-299
77. Showell, H. J., Pettipher, E. R., Cheng, J. B., Breslow, R., Conklyn, M. J., Farrell, C. A., Hingorani, G. P., Salter, E. D., Hackman, B. C., and Wimberly, D. J. 1995, The in vitro and in vivo pharmacologic activity of the potent and selective leukotriene B4 receptor antagonist CP-105696 J. Pharmacol. Exp. Ther. 273, 176-184
78. Butler, S., Hall, F. R., and Sanford, H. N. (1950) An investigation of the mode of action of benadryl as an antihistaminic J. Lab. Clin. Med. 36, 806
79. Rago, B., Liu, J., Tan, B., and Holliman, C. (2011) Application of the dried spot sampling technique for rat cerebrospinal fluid sample collection and analysis J. Pharm. Biomed. Anal. 55, 1201-1207
80. Bednar, M., Chieffo, C., Morse, T., Duplin, M., and Gibbs, M. (2004) Plasma and cerebrospinal fluid (CSF) pharmacokinetics of CP-457,920, a selective alpha 5 GABA-A receptor inverse agonist in young, healthy volunteers Clin. Pharmacol. Ther. 75, 90
81. Gauthier, D. R., Jr., Limanto, J., Devine, P. N., Desmond, R. A., Szumigala, R. H., Jr., Foster, B. S., and Volante, R. P. (2005) Palladium-catalyzed regioselective arylation of imidazo[1,2-b][1,2,4]triazine: synthesis of an alpha 2/3-selective GABA agonist J. Org. Chem. 70, 5938-5945
82. Zhu, C., Hansen, A. R., Bateman, T., Chen, Z., Holt, T. G., Hubert, J. A., Karanam, B. V., Lee, S. J., Pan, J., Qian, S., Reddy, V. B., Reitman, M. L., Strack, A. M., Tong, V., Weingarth, D. T., Wolff, M. S., MacNeil, D. J., Weber, A. E., Duffy, J. L., and Edmondson, S. D. (2008) Discovery of imidazole carboxamides as potent and selective CCK1R agonists Bioorg. Med. Chem. Lett. 18, 4393-4396
83. McLean, S., Ganong, A., Seymour, P. A., Bryce, D. K., Crawford, R. T., Morrone, J., Reynolds, L. S., Schmidt, A. W., Zorn, S., Watson, J., Fossa, A., DePasquale, M., Rosen, T., Nagahisa, A., Tsuchiya, M., and Heym, J. (1996) Characterization of CP-122,721; a nonpeptide antagonist of the neurokinin NK1 receptor J. Pharmacol. Exp. Ther. 277, 900-908
84. Kelly, J. (2009) Appendices, in Principles of CNS Drug Development: From Test Tube to Patient pp 287-293, John Wiley & Sons, Ltd., Chichester, U.K.
85. Metro, T. X., Cochi, A., Gomez Pardo, D., and Cossy, J. (2011) Asymmetric synthesis of an antagonist of neurokinin receptors: SSR 241586 J. Org. Chem. 76, 2594-2602
86. Croci, T., Cecchi, R., Marini, P., Rouget, C., Viviani, N., Germain, G., Guagnini, F., Fradin, Y., Descamps, L., Pascal, M., Advenier, C., Breuiller-Fouche, M., Leroy, M. J., and Bardou, M. (2007) In vitro and in vivo pharmacological characterization of ethyl-4-[trans-4-[((2S)-2-hydroxy-3-[4- hydroxy-3[(methylsulfonyl)amino]-phenoxy]p ropyl) amino]cyclohexyl]benzoate hydrochloride (SAR150640), a new potent and selective human beta3-adrenoceptor agonist for the treatment of preterm labor J. Pharmacol. Exp. Ther. 321, 1118-1126
87. Walsh, S. L., Strain, E. C., Abreu, M. E., and Bigelow, G. E. (2001) Enadoline, a selective kappa opioid agonist: comparison with butorphanol and hydromorphone in humans Psychopharmacology (Berlin, Ger.) 157, 151-162
88. Gray, J. A. and Roth, B. L. (2007) The pipeline and future of drug development in schizophrenia Mol. Psychiatry 12, 904-922
89. Mente, S., Gallaschun, R., Schmidt, A., Lebel, L., Vanase-Frawley, M., and Fliri, A. (2008) Quantitative structure-activity relationship of phenoxyphenyl-methanamine compounds with 5HT2A, SERT, and hERG activities Bioorg. Med. Chem. Lett. 18, 6088-6092
90. Middleton, D. S., Andrews, M., Glossop, P., Gymer, G., Hepworth, D., Jessiman, A., Johnson, P. S., MacKenny, M., Stobie, A., Tang, K., Morgan, P., and Jones, B. (2008) Designing rapid onset selective serotonin re-uptake inhibitors. Part 3: Site-directed metabolism as a strategy to avoid active circulating metabolites: structure-activity relationships of (thioalkyl)phenoxy benzylamines Bioorg. Med. Chem. Lett. 18, 5303-5306
91. Bromidge, S. M., Dabbs, S., Davies, D. T., Davies, S., Duckworth, D. M., Forbes, I. T., Gaster, L. M., Ham, P., Jones, G. E., King, F. D., Mulholland, K. R., Saunders, D. V., Wyman, P. A., Blaney, F. E., Clarke, S. E., Blackburn, T. P., Holland, V., Kennett, G. A., Lightowler, S., Middlemiss, D. N., Trail, B., Riley, G. J., and Wood, M. D. (2000) Biarylcarbamoylindolines are novel and selective 5-HT(2C) receptor inverse agonists: identification of 5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl] -6-trifluoromethylindoline (SB-243213) as a potential antidepressant/anxiolytic agent J. Med. Chem. 43, 1123-1134
92. Knight, A. R., Misra, A., Quirk, K., Benwell, K., Revell, D., Kennett, G., and Bickerdike, M. (2004) Pharmacological characterisation of the agonist radioligand binding site of 5-HT(2A), 5-HT(2B) and 5-HT(2C) receptors Naunyn-Schmiedeberg's Arch. Pharmacol. 370, 114-123
93. Ashcroft, F. J., Newberg, J. Y., Jones, E. D., Mikic, I., and Mancini, M. A. (2011) High content imaging-based assay to classify estrogen receptor-alpha ligands based on defined mechanistic outcomes Gene 477, 42-52
94. Luo, G., Cunningham, M., Kim, S., Burn, T., Lin, J., Sinz, M., Hamilton, G., Rizzo, C., Jolley, S., Gilbert, D., Downey, A., Mudra, D., Graham, R., Carroll, K., Xie, J., Madan, A., Parkinson, A., Christ, D., Selling, B., LeCluyse, E., and Gan, L. S. (2002) CYP3A4 induction by drugs: correlation between a pregnane X receptor reporter gene assay and CYP3A4 expression in human hepatocytes Drug Metab. Dispos. 30, 795-804
95. Le Fur, G., Vaucher, N., Perrier, M. L., Flamier, A., Benavides, J., Renault, C., Dubroeucq, M. C., Gueremy, C., and Uzan, A. (1983) Differentiation between two ligands for peripheral benzodiazepine binding sites, [3H]RO5-4864 and [3H]PK 11195, by thermodynamic studies Life Sci. 33, 449-457