High-affinity α-aminobutyric acid A/benzodiazepine ligands: Synthesis and structure - Activity relationship studies of a new series of tetracyclic imidazoquinoxalines

Journal of Medicinal Chemistry

Volumn 39, Issue 23, 1996, Pages 4654-4666

  Mickelson, John W ^b   Jacobsen, E Jon ^a   Carter, Donald B ^a   Im, Haesook K ^a   Im, Wha Bin ^a   Schreur, Peggy J K D ^a   Sethy, Vimala H ^a   Tang, Andy H ^a   McGee, James E ^a   Petke, James D ^a  

^a PFIZER INC   (United States)

^b 3M COMPANY   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

1 (5 CYCLOPROPYL 1,2,4 OXADIAZOL 3 YL) 12,12A DIHYDROIMIDAZO[1,5 A]PYRROLO[2,1 C]QUINOXALIN 10(11H) ONE; 3 (5 CYCLOPROPYL 1,2,4 OXADIAZOL 3 YL) 5 [(DIMETHYLAMINO)CARBONYL] 4,5 DIHYDROIMIDAZO[1,5 A]QUINOXALINE; BENZODIAZEPINE DERIVATIVE; PENTETRAZOLE; RECEPTOR SUBTYPE; U 89267; U 91571; UNCLASSIFIED DRUG;

ANIMAL CELL; ANIMAL TISSUE; ANTICONVULSANT ACTIVITY; ARTICLE; DRUG EFFICACY; LIGAND BINDING; NONHUMAN; RAT; RECEPTOR AFFINITY; STRUCTURE ACTIVITY RELATION; STRUCTURE ANALYSIS; TRANQUILIZING ACTIVITY;

ANIMALS; CELL LINE; HUMANS; LIGANDS; MAGNETIC RESONANCE SPECTROSCOPY; MALE; MASS SPECTROMETRY; MEMBRANE POTENTIALS; MICE; MOLECULAR CONFORMATION; NUCLEOPOLYHEDROVIRUS; QUINOXALINES; RATS; RECEPTORS, GABA-A; RECOMBINANT PROTEINS; SEIZURES; SPECTROPHOTOMETRY, INFRARED; SPODOPTERA; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 10544251444     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm960401i     Document Type: Article

References (55)

1. For recent reviews see: (a) Gardner, C. R. A Review of Recently-Developed Ligands for Neuronal Benzodiazepine Receptors and Their Pharmacological Activities. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 1992, 16, 755-781. (b) Gammill, R. B.; Carter, D. B. Neuronal BZD Receptors: New Ligands, Clones and Pharmacology. In Annual Reports Medicinal Chemistry; Bristol, J. A., McCall, J. M., Eds.; Academic Press: New York, 1993; Vol. 28, pp 19-27.
2. For recent reviews see: (a) Gardner, C. R. A Review of Recently-Developed Ligands for Neuronal Benzodiazepine Receptors and Their Pharmacological Activities. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 1992, 16, 755-781. (b) Gammill, R. B.; Carter, D. B. Neuronal BZD Receptors: New Ligands, Clones and Pharmacology. In Annual Reports Medicinal Chemistry; Bristol, J. A., McCall, J. M., Eds.; Academic Press: New York, 1993; Vol. 28, pp 19-27.
3. - Ion Channels Modulated by Multiple Drug-Binding Sites. TiPS 1992, 13, 446-450.
4. (a) Squires, R., Ed. GABA and Benzodiazepine Receptors; CRC Press: Boca Raton, FL, 1988; Vol. I, II.
5. (b) Haefely, W. In Benzodiazepines; Beaumont, G., Brandon, S., Leonard, B. E., Eds.; John Wiley and Sons: New York, 1990; pp 1-18.
6. (c) Haefely, W. Partial Agonists of the Benzodiazepine Receptor: From Animal Data to Results in Patients. In Chloride Channels and Their Modulation by Neurotransmitters and Drugs; Biggio, G., Costa, E., Eds.; Raven Press: New York, 1988; pp 275-292.
7. (a) Gardner, C. R. Functional In Vivo Correlates of the Benzodiazepine Agonist-Inverse Agonist Continuum. Prog. Neurobiol. 1988, 31, 425-476.
8. (b) Braestrup, C.; Nielsen, M. In Receptor Biochemistry and Methodology; Olsen, R. W., Venter, J. C., Eds.; A. R. Liss, Inc.: New York, 1986; Vol. 5, p 167.
9. (c) Bare, T. M.; Resch, J. F.; Patel, J. B. Anxiolytics and Sedative-Hypnotics. In Annual Reports Medicinal Chemistry; Bailey, D. M., Ed.; Academic Press: New York, 1987; Vol. 22, pp 11-20.
10. (d) Haefely, W.; Kyburz, E.; Gerecke, M.; Mohler, H. Recent Advances in the Molecular Pharmacology of Benzodiazepine Receptors and in the Structure-Activity Relationships of Their Agonists and Antagonists. In Advances in Drug Research; Testa, B., Ed.; Academic Press: New York, 1985; Vol. 14, pp 165-322.
11. (e) Braestrup, C.; Honore, T.; Nielsen, M.; Petersen, E. N.; Jensen, L. H. Ligands for Benzodiazepine Receptors With Positive and Negative Efficacy. Biochem. Pharmacol. 1984, 33, 859-862.
12. (a) Petersen, E. N.; Jensen, L. H.; Diejer, J.; Honore, T. New Perspectives in Benzodiazepine Receptor Pharmacology. Pharmacopsychiatry 1986, 19, 4-6.
13. (b) Haefely, W. Psychopharmacology of Anxiety. Eur. Neuropsychopharmacol. 1991, 1, 89-95.
14. Skolnick, P.; Wong, G. In Imidazopyridines in Anxiety Disorders: A Novel Experimental and Therapeutic Approach; Zivkovic, B., Langer, S., Bartholini, G., Eds.; Raven Press: New York, 1992.
15. A Receptor Subunit for Benzodiazepine Pharmacology. Nature 1989, 338, 582-585.
16. (b) Pritchett, D. B.; Seeburg, P. H. γ-Aminobutyric Acid Type A Receptor Point Mutation Increases the Affinity of Compounds for the Benzodiazepine Site. Proc. Natl. Acad Sci. U.S.A. 1991, 88, 1421-1426.
17. 5-Subunit Creates Novel Type II Benzodiazepine Receptor Pharmacology. J. Neurochem. 1990, 54, 1802-1804.
18. A-Benzodiazepine Receptors Produced in Transfected Cells. Science 1989, 245, 1389-1392.
19. A Receptor Selective for a Behavioral Alcohol Antagonist. Nature 1990, 346, 648-651.
20. A Receptors in Transfected Human Embryonic Kidney Cells. Neurosci. Lett. 1991, 130, 169-172.
21. - Currents. Mol. Pharmacol. 1991, 39, 691-696.
22. (a) Tang, A. H.; Franklin, S. R.; Himes, C. S.; Ho, P. M. Behavioral Effects of U-78875, a Quinoxalinone Anxiolytic with Potent Benzodiazepine Antagonist Activity. J. Pharmacol. Exp. Ther. 1991, 259, 248-254.
23. A Receptors. Mol. Pharmacol. 1992, 42, 294-301.
24. A/Benzodiazepine Receptor Complex. J. Med. Chem. 1996, 39, 158-175.
25. A/Benzodiazepine Receptor. J. Med. Chem. 1994, 37, 758-768.
26. A Receptors. Br. J. Pharmacol. 1993, 110, 677-680.
27. Meyers, A. I.; Fleming, M. P. Photoassisted Cristol-Firth-Hunsdiecker Reaction. J. Org. Chem. 1979, 44, 3405-3406.
28. An alternative preparation for this compound has been reported, although no spectral data were provided. Liedholm, B. Copper(I) Catalyzed Replacement of Bromine by Chloride Ion in Halonitrobenzenes. Acta Chem. Scand. 1969, 23, 3175-3186.
29. Watjen, F.; Baker, R.; Engelstoff, M.; Herbert, R.; MacLeod, A.; Knight, A.; Merchant, K.; Moseley, J.; Saunders, J.; Swain, C. J.; Wong, E.; Springer, J. P. Novel Benzodiazepine Receptor Partial Agonists: Oxadiazolylimidazobenzodiazepines. J. Med. Chem. 1989, 32, 2282-2291.
30. Manimaran, T.; Thiruvengadam, T. K.; Ramakrishnan, V. T. Synthesis of Coumarins (2-Oxo-2H-1-benzopyrans), Thiacoumarins (2-Oxo-2H-1-benzothiopyrans), and Carbostyrils (2-Oxo-1,2-dihydroquinolines). Synthesis 1975, 739-741.
31. For a general route into substituted quinoxalin-2(1H)-ones see: Olagbemiro, T. O.; Nyakutse, C. A.; Lajide, L.; Agho, M. O.; Chukwu, C. E. Synthesis and Reactions of 3-Phenyl-3,4-dihydro-1,4-quinoxalin-2(1H)-one and its Heterocyclic Analogues. Bull. Soc. Chim. Belg. 1987, 96, 473-480.
32. Regitz, M.; Hocker, J.; Leidhegener, A. In Organic Syntheses; Wiley: New York, 1973; Collect. Vol. V, pp 179-183.
33. Boyer, J. H.; Mack, C. H.; Goebel, N.; Morgan, L. R., Jr. Reactions of Sodium Phenylacetylide and Sodium Alkoxide with Tosyl and Mesyl Azides. J. Org. Chem. 1958, 23, 1051-1053.
34. Johnson, S. A.; Hunt, H. R.; Neumann, H. M. Preparation and Properties of Anhydrous Rhodium(II) Acetate and Some Adducts Thereof. Inorg. Chem. 1963, 2, 960-962.
35. Romero, A. G.; Darlington, W. H.; Mickelson, J. M.; Jacobsen, E. J. Oxidative Cyclization of Acyclic Ureas with Bis(trifluoroacetoxy)iodobenzene to Generate N-Substituted 2-Benzimidazolinones. Tetrahedron Lett. 1996, 37, 2361-2364.
36. Sethy, V. H.; Harris, D. W. Determination of Biological Activity of Alprazolam, Triazolam and Their Metabolites. J. Pharm. Pharmacol. 1982, 34, 115-116.
37. - Uptake in Rat Cerebrocortical Membranes. Mol. Pharmacol. 1991, 39, 394-398.
38. - Uptake in Rat Brain Synaptoneurosomes: Evidence for Rapid Desensitization of the GABA Receptor-Coupled Chloride Ion Channel. Mol. Pharmacol. 1986, 30, 419-426.
39. A Receptors. Mol. Pharmacol. 1993, 44, 866-870.
40. Rudzik, A. D.; Hester, J. B.; Tang, A. H.; Straw, R. N.; Friis, W. Triazolobenzodiazepines, A New Class of Central Nervous System-Depressant Compounds. In The Benzodiazepines; Garattini, S., Mussini, E., Randall, L. O., Eds.; Raven Press: New York, 1973; pp 285-297.
41. 50s in the range of 0.17-4.5 mg/kg.
42. A Chloride Channels and Benzodiazepine Binding Sites in Baculovirus Infected Insect Cells. Bio / Technology 1992, 10, 679-681.
43. A Receptor Subunits in a Human Kidney Cell Line. Neurosci. Lett. 1993, 153, 206-209.
44. Mohamadi, F.; Richards, N. G. J.; Guida, W. C.; Liskamp, R.; Lipton, M.; Caufield, C.; Chang, G.; Hendrickson, T.; Still, W. C. MacroModel- An Integrated Software System for Modeling Organic and Bioorganic Molecules Using Molecular Mechanics. J. Comput. Chem. 1990, 11, 440-467.
45. Weiner, S. J.; Kollman, P. A.; Nguyen, D. T.; Case, D. A. An All Atom Force Field for Simulations of Proteins and Nucleic Acids. J. Comput. Chem. 1986, 7, 230-252.
46. 2 Torsional Terms. J. Am. Chem. Soc. 1977, 99, 8127-8134.
47. Chang, G.; Guida, W. C.; Still, W. C. An Internal Coordinate Monte Carlo Method for Searching Conformational Space. J. Am. Chem. Soc. 1989, 111, 4379-4386.
48. Lipton, M.; Still, W. C. The Multiple Minimum Problem in Molecular Modeling: Tree Searching Internal Coordinate Conformational Space. J. Comput. Chem. 1988, 9, 343-355.
49. A/Benzodiazepine Receptor Complex. J. Med. Chem. 1996, 39, 3820-3836.
50. Tebib, S.; Bourguignon, J.-J.; Wermuth, C.-G. The Active Analog Approach Applied to the Pharmacophore Identification of Benzodiazepine Receptor Ligands. J. Comput.-Aided Mol. Des. 1987, 1, 153-170.
51. Gardner, C. R. A Review of Recently-Developed Ligands for Neuronal Benzodiazepine Receptors and Their Pharmacological Activities. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 1992, 16, 755-781.
52. Zhang, W.; Koehler, K. F.; Zhang, P.; Cook, J. M. Development of a Comprehensive Pharmacophore Model for the Benzodiazepine Receptor. Drug Des. Discovery 1995, 12, 193-248.
53. Schove, L. T.; Perez, J. J.; Loew, G. H. Molecular Determinants of Recognition and Activation at the Cerebellar Benzodiazepine Receptor Site. Bioorg. Med. Chem. 1994, 2, 1029-1049.
54. 1H NMR integration of the doublet at δ 7.03 for 11 and the corresponding doublet at δ 7.62 for 10.
55. 1H NMR integration of the doublet at δ 7.94 for 35 and the corresponding doublet at δ 7.56 for the uncyclized intermediate.