Activity of B-nor analogues of neurosteroids on the GABAA receptor in primary neuronal cultures

Journal of Medicinal Chemistry

Volumn 49, Issue 11, 2006, Pages 3225-3234

  Suñol, Cristina ^a   García, Daniel A ^a   Bujons, Jordi ^b   Krištofíková, Zdena ^c   Matyas, Libor ^c   Babot, Zoila ^a   Kasal, Alexander ^c  

^a INST D INVESTIGACIONS B   (Spain)

^b DEPARTMENT OF ENVIRONMENTAL CHEMISTRY   (Spain)

^c INSTITUTE OF ORGANIC CHEMISTRY AND BIOCHEMISTRY   (Czech Republic)

Author keywords

[No Author keywords available]

Indexed keywords

20 OXO 7 NORPREGN 5 EN 3BETA YL METHANESULFONATE; 3ALPHA HYDROXY 5ALPHA PREGNAN 20 ONE; 3ALPHA HYDROXY 5ALPHA PREGNANE 7,20 DIONE; 3ALPHA HYDROXY 7 NOR 5BETA PREGNAN 20 ONE; 3ALPHA,6ALPHA DIHYDROXY 5 METHYL 7,19 DINOR 5BETA PREGN 9 EN 20 ONE; 4 AMINOBUTYRIC ACID A RECEPTOR; 4 AMINOBUTYRIC ACID A RECEPTOR BLOCKING AGENT; 5,6ALPHA OXIDO 20 OXO 7 NOR 5ALPHA PREGNAN 3ALPHA OL; 5,6ALPHA OXIDO 20 OXO 7 NOR 5ALPHA PREGNAN 3BETA YL METHANESULFONATE; BARBITURIC ACID DERIVATIVE; BENZODIAZEPINE DERIVATIVE; DIAZEPAM; ELTANOLONE; FLUNITRAZEPAM; NEUROSTEROID; NORALLOPREGNANOLONE B; UNCLASSIFIED DRUG;

ARTICLE; CHLORIDE TRANSPORT; DRUG RECEPTOR BINDING; NERVE CELL CULTURE; NEUROTOXICITY; PHARMACOPHORE;

ANIMALS; ANIONS; CELL SURVIVAL; CELLS, CULTURED; CHLORIDES; COMPUTER SIMULATION; GABA MODULATORS; MALE; MODELS, MOLECULAR; NEOCORTEX; NEURONS; PREGNANOLONE; RADIOLIGAND ASSAY; RATS; RATS, WISTAR; RECEPTORS, GABA-A; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 33744800553     PISSN: 00222623     EISSN: None     Source Type: Journal    
DOI: 10.1021/jm060002f     Document Type: Article

References (62)

1. A receptor channels. Annu. Rev. Neurosci. 1994, 17, 569-602.
2. Dalby, N. O. Inhibition of gamma-aminobutyric acid uptake: anatomy, physiology and effects against epileptic seizures. Eur. J. Pharmacol. 2003, 479, 127-137.
3. Fritschy, J. M.; Brünig, I. Formation and plasticity of GABAergic synapses: physiological mechanisms and pathophysiological implications. Pharmacol. Ther. 2003, 98, 299-323.
4. A receptors. Prog. Neurobiol. (Amsterdam, Neth.) 2003, 71, 67-80.
5. Reddy, D. S. Is there a physiological role for the neurosteroid THDOC in stress-sensitive conditions? Trends Pharmacol. Sci. 2003, 24, 103-106.
6. A receptor subtypes in the brain: a paradigm for CNS drug discovery? Drug Discovery Today 2003, 8, 445-450.
7. Hill, M.; Popov, P.; Havlíková, H.; Kancheva, L.; Vrbíková, J.; Kancheva, R.; Pouzar, V.; Černý, I.; Stárka, L. Altered profiles of serum neuroactive steroids in premenopausal women treated for alcohol addiction. Steroids 2005, 70, 515-524.
8. A Receptors. In Pharmacology of GABA and Glycine Neurotransmisson; Möhler, H1, Ed.; Springer: Berlin, Germany, 2001.
9. A receptor in primary cultures of mouse cortical neurons. Neuropharmacology 2006, 50, 25-35.
10. Norberg, L.; Backstrom, T.; Wahlstrom, G. Anesthetic effects of pregnanolone in combination with allopregnanolone, thiopental, hexobarbital and flurazepam: an EEG study in the rat. Br. J. Anaesth. 1999, 82, 731-737.
11. Khisti, R. T.; Chopde, C. T.; Jain, S. P. Antidepressant-like effect of the neurosteroid 3alpha-hydroxy-5alpha-pregnan-20-one in mice forced swim test. Pharmacol., Biochem. Behav. 2000, 67, 137-143.
12. Czlonkowska, A. I.; Krzascik, P.; Sienkiewicz-Jarosz, H.; Siemiatkowski, M.; Szyndler, J.; Bidzinski, A.; Plaznik, A. The effects of neurosteroids on picrotoxin-, bicuculline- and NMDA-induced seizures, and a hypnotic effect of ethanol. Pharmacol., Biochem. Behav. 2000, 67, 345-353.
13. Slavíková, B.; Kasal, A.; Uhlîŕová, L.; Kršiak, M.; Chodounská, H.; Kohout, L. Suppressing aggressive behavior with analogues of allopregnanolone (epalon). Steroids 2001, 66, 99-105.
14. A receptor function and seizure susceptibility. J. Neurosci. 2002, 22, 3795-3805.
15. Kralic, J. E.; Wheeler, M.; Renzi, K.; Ferguson, C.; O'Buckley, T. K.; Grobin, A. C.; Morrow, A. L.; Homanics, G. E. Deletion of GABAA receptor alpha 1 subunit-containing receptors alters responses to ethanol and other anesthetics. J. Pharmacol. Exp. Ther. 2003, 305, 600-607.
16. Schumacher, M.; Weill-Engerer, S.; Liere, P.; Robert, F.; Franklin, R. J. M.; Garcia-Segura, L. M.; Lambert, J. J.; Mayo, W.; Melcangi, R. C.; Parducz, A.; Suter, U.; Carelli, C.; Baulieu, E. E.; Akwa, Y. Steroid hormones and neurosteroids in normal and pathological aging of the nervous system. Prog. Neurobiol. 2003, 71, 3-29.
17. Griffin, L. D.; Gong, W.; Verot, L.; Mellon, S. H. Niemann-Pick type C disease involves disrupted neurosteroidogenesis and responds to allopregnanolone. Nat. Med. 2004, 10, 704-711.
18. He, J.; Hoffman, S. W.; Stein, D. G. Allopregnanolone, a progesterone metabolite, enhances behavioral recovery and decreases neuronal loss after traumatic brain injury. Restor. Neurol. Neurosci. 2004, 22, 19-31.
19. Harrison, N. L.; Majewska, M. D.; Harrington, J. W.; Barker, J. L. Structure-activity relationships for steroid interaction with the gamma-aminobutyric acidA receptor complex. J. Pharmacol. Exp. Ther. 1987, 241, 346-353.
20. A receptors in cultured hippocampal neurons and transfected HEK-293 cells. Neuropharmacology 1996, 35, 1161-1168.
21. A receptors by pregnanediols. Neuropharmacology 1996, 35, 1223-1231.
22. Hawkinson, J. E.; Acosta-Burruel, M.; Yang, K. C.; Hogenkamp, D. J.; Chen, J. S.; Lan, N. C.; Drewe, J. A.; Whittemore, E. R.; Woodward, R. M.; Carter, R. B.; Upasani, R. B. Substituted 3beta-phenylethynyl derivatives of 3alpha-hydroxy-5alpha-pregnan-20-one: remarkably potent neuroactive steroid modulators of gamma-aminobutyric acidA receptors. J. Pharmacol. Exp. Ther. 1998, 287, 198-207.
23. Jiang, X.; Manion, B. D.; Benz, A.; Rath, N. P.; Evers, A. S.; Zorumski, C. F.; Mennerick, S.; Covey, D. F. Neurosteroid analogues. 9. Conformationally constrained pregnanes: structure-activity studies of 13, 24-cyclo-18,21- dinorcholane analogues of the GABA modulatory and anesthetic steroids (3alpha,5alpha)- and (3alpha,5beta)-3-hydroxypregnan-20-one. J. Med. Chem. 2003, 46, 5334-5348.
24. Gasior, M.; Ungard, J. T.; Beekman, M.; Carter, R. B.; Witkin, J. M. Acute and chronic effects of the synthetic neuroactive steroid, ganaxolone, against the convulsive and lethal effects of pentylenetetrazol in seizure-kindled mice: comparison with diazepam and valproate. Neuropharmacology 2000, 39, 1184-1196.
25. Luconi, M.; Francavilla, F.; Porazzi, I.; Macerola, B.; Forti, G.; Baldi, E. Human spermatozoa as a model for studying membrane receptors mediating rapid nongenomic effects of progesterone and estrogens. Steroids 2004, 69, 553-559.
26. A receptors. J. Med. Chem. 1996, 39, 4218-4232.
27. A receptor function by neuroactive steroids. Brain Res. 1999, 819, 75-82.
28. A receptors. J. Med. Chem. 2000, 43, 4118-4125.
29. Eduardo, S. L.; Ghini, A. A.; Burton, G. Oxido-bridged neurosteroid analogues. Synthesis of 2,19-oxido-allopregnanolone. ARKIVOC (Gainesville, FL, U.S.) 2003, 468-476.
30. Zeng, C. M.; Manion, B. D.; Benz, A.; Evers, A. S.; Zorumski, C. F.; Mennerick, S.; Covey, D. F. Neurosteroid analogues. 10. The effect of methyl group substitution at the C-6 and C-7 positions on the GABA modulatory and anesthetic actions of (3alpha,5alpha)- and (3alpha,5beta)-3-hydroxypregnan-20- one. J. Med. Chem. 2005, 48, 3051-3059.
31. Poletti, A.; Martini, L. Androgen-activating enzymes in the central nervous system. J. Steroid Biochem. Mol. Biol. 1999, 69, 117-122.
32. Dorfman, R. I.; Fajkoš, J.; Joska, J. Biological activity of various steroids including B-norsteroids. Steroids 1964, 3, 675-685.
33. Vale, C.; Vilaró, M. T.; Rodríguez-Farré, E.; Suñol, C. Effects of the conformationally restricted GABA analogs, cis- and trans-4-aminocrotonic acid, on GABA neurotransmission in primary neuronal cultures. J. Neurosci. Res. 1999, 57, 95-105.
34. Butenandt, A.; Heusner, A. About epipregn-5-enol-(e)-one-(20). Chem. Ber. 1939, 72, 1118-1121.
35. Schubert, A.; Zepter, R. Steroids from Hyodeoxycholic Acid: Allopregnan-3β-ol-6,20-dione and its 20-monoketal. J. Prakt. Chem. 1964, 26, 159-167.
36. Kasal, A. Synthesis of 7-norallopregnanolone. Collect. Czech. Chem. Commun. 1999, 64, 1471-1478.
37. Kasal, A. 6-Substituted derivatives of 7-norallopregnanolone. Tetrahedron 2000, 56, 3559-3565.
38. Kasal, A.; Matyáš, L.; Buděší nský, M. Neurosteroid analogues: synthesis of 6-aza-allopregnanolone. Tetrahedron 2005, 61, 2269-2278.
39. 3H] flunitrazepam binding and gamma-aminobutyric acidA receptor function. Mol. Pharmacol. 1994, 46, 977-985.
40. A receptors by 5alpha-pregnan-3alpha-ol-20-one in the rat brain regions. Brain Res. 1999, 832, 164-167.
41. a receptors. Collect. Czech. Chem. Commun. 2002, 67, 30-46.
42. A receptor modulates the benzodiazepine binding site in primary cultures of mouse cerebellar granule cells. Neuropharmacology 2001, 41, 819-833.
43. Purdy, R. H.; Morrow, A. L.; Blinn, J. R.; Paul, S. M. Synthesis, metabolism, and pharmacological activity of 3alpha-hydroxy steroids which potentiate GABA-receptor-mediated chloride ion uptake in rat cerebral cortical synaptoneurosomes. J. Med. Chem. 1990, 33, 1572-1581.
44. A receptor activity of 6-oxa-analogs of neurosteroids. Steroids 2000, 65, 349-356.
45. Pomés, A.; Rodríguez-Farré, E.; Suñol, C. Disruption of GABA-dependent chloride flux by cyclodienes and hexachlorocyclohexanes in primary cultures of cortical neurons. J. Pharmacol. Exp. Ther. 1994, 271, 1616-1623.
46. A receptor. Curr. Top. Med. Chem. 2002, 2, 887-902.
47. A receptor activity of a 6,19-oxido analog of pregnanolone. Bioorg. Med. Chem. Lett. 2003, 13, 343-346.
48. Morrow, A. L.; Pace, J. R.; Purdy, R, H.; Paul, S. M. Characterization of steroid interactions with γ-aminobutyric acid receptor-gated chloride ion channels: Evidence for multiple steroid recognition sites. Mol. Pharm. 1990, 37, 263-270.
49. A receptors. Mol. Pharm. 2004, 65, 1191-1197.
50. A receptor modulation and anesthesia. J. Pharm. Exp. Ther. 2000, 293, 1009-116.
51. Hubert, C.; Alexandre, C.; Aubertin, A. M.; Huet, F. An efficient synthesis of dienic nucleoside analogs via a Mitsunobu reaction. Tetrahedron 2003, 59, 3127-3130.
52. A receptors. J. Neurosci. Res. 1998, 52, 276-285.
53. A receptors and niflumic acid-sensitive chloride channels. Eur. J. Neurosci. 2005, 21, 103-112.
54. Halgren, T. A. MMFF VI. MMFF94s option for energy minimization studies. J. Comput. Chem. 1999, 20, 720-729.
55. Halgren, T. A. MMFF VII. Characterization of MMFF94, MMFF94s, and other widely available force fields for conformational energies and for intermolecular-interaction energies and geometries J. Comput. Chem. 1999, 20, 730-748.
56. Goodford, P. J. A computational procedure for determining energetically favorable binding sites on biologically important macromolecules. J. Med. Chem. 1985, 28, 849-857.
57. Boobbyer, D. N.; Goodford, P. J.; McWhinnie, P. M.; Wade, R. C. New hydrogen-bond potentials for use in determining energetically favorable binding sites on molecules of known structure. J. Med. Chem. 1989, 32, 1083-1094.
58. Wei, B. Q.; Baase, W. A.; Weaver, L. H.; Matthews, B. W.; Shoichet, B. K. A model binding site for testing scoring functions in molecular docking. J. Mol. Biol. 2002, 322, 339-355.
59. Li, J. B.; Zhu, T. H.; Cramer, C. J.; Truhlar, D. G. New class IV charge model for extracting accurate partial charges from wave functions. J. Phys. Chem. A 1998, 102, 1820-1831.
60. Chambers, C. C.; Hawkins, G. D.; Cramer, C. J.; Truhlar, D. G. Model for aqueous solvation based on class IV atomic charges and first solvation shell effects. J. Phys. Chem. 1996, 100, 16385-16398.
61. Clement, O. A.; Mehl, A. T. HipHop: Pharmacophores based on multiple common-feature alignments. In Pharmacophore Perception. Development and Use in Drug Design, 1st ed.; Güner, O. F., Ed.; International University Line: La Jolla, CA, 2000; pp 69-82.
62. This value was chosen, rather than the default 20 kcal/mol value, to avoid a bias toward high energy conformations in the alignments of the compounds considered along the process of building the pharmacophoric hypotheses.