Characterization of the anticonvulsant properties of Ganaxolone (CCD 1042; 3α-hydroxy-3β-methyl-5α-pregnan-20-one), a selective, high-affinity, steroid modulator of the γ-aminobutyric acid(A) receptor

Journal of Pharmacology and Experimental Therapeutics

Volumn 280, Issue 3, 1997, Pages 1284-1295

  Carter, Richard B ^a   Wood, Paul L ^a   Wieland, Scott ^a   Hawkinson, Jon E ^a   Belelli, Delia ^b   Lambert, Jeremy J ^b   White, H Steve ^c   Wolf, Harold H ^c   Mirsadeghi, Seid ^a   Tahir, S Hasan ^a   Bolger, Michael B ^d   Lan, Nancy C ^a   Gee, Kelvin W ^e  

^a Department of Pharmacokinetics and Drug Metabolism   (United States)

^b UNIVERSITY OF DUNDEE   (United Kingdom)

^c UNIVERSITY OF UTAH   (United States)

^d UNIVERSITY OF SOUTHERN CALIFORNIA   (United States)

^e UNIVERSITY OF CALIFORNIA   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

3ALPHA HYDROXY 5ALPHA PREGNAN 20 ONE; 4 AMINOBUTYRIC ACID RECEPTOR; AMINOPHYLLINE; BENZODIAZEPINE; BICUCULLINE; FLUNITRAZEPAM; GABOXADOL; GANAXOLONE; MUSCIMOL; PENTETRAZOLE;

ALLOSTERISM; ANIMAL EXPERIMENT; ANIMAL TISSUE; ANTICONVULSANT ACTIVITY; ARTICLE; BINDING AFFINITY; ELECTRIC SHOCK; ENZYME INHIBITION; EPILEPSY; LIGAND BINDING; NONHUMAN; PRIORITY JOURNAL; RAT; RECEPTOR BINDING; SEIZURE; STEROID BLOOD LEVEL; STRUCTURE ACTIVITY RELATION; XENOPUS LAEVIS;

ANIMALS; ANTICONVULSANTS; BICYCLO COMPOUNDS, HETEROCYCLIC; CEREBRAL CORTEX; FLUNITRAZEPAM; GABA MODULATORS; HUMANS; KINDLING, NEUROLOGIC; MICE; PREGNANOLONE; RADIOLIGAND ASSAY; RATS; RATS, SPRAGUE-DAWLEY; RECEPTORS, GABA-A; RECOMBINANT PROTEINS; SEIZURES;

EID: 14444270606     PISSN: 00223565     EISSN: None     Source Type: Journal    
DOI: None     Document Type: Article

References (77)

1. ALDENKAMP, A. P., VERMEULEN, J., MULDER, O. G., OVERWEG, J., VAN PARYS, A. P., BEUN, A. M. AND VAN 'T SLOT, B.: γ-Vinyl GABA (vigabatrin) and mood disturbances. Epilepsia 35: 999-1004, 1994.
2. BARKER, J. L. AND RANSOM, B. R.: Pentobarbitone pharmacology of mammalian central neurones grown in tissue culture. J. Physiol. (Lond.) 280: 355-372, 1978.
3. BELELLI, D., BOLGER, M. B. AND GEE, K. W.: Anticonvulsant profile of the progesterone metabolite 5α-pregnan-3α-ol-20-one. Eur. J. Pharmacol. 166: 325-329, 1989.
4. BELELLI, D., LAN, N. C. AND GEE, K. W.: Anticonvulsant steroids and the GABA/benzodiazepine receptor-chloride ionophore complex. Neurosci. Biobehav. Rev. 14: 315-322, 1990.
5. CHEN, R. T., BELELLI, D., LAMBERT, J. J., PETERS, J. A., REYES, A. AND LAN, N. C.: Cloning and functional expression of a Drosophila gamma-aminobutyric acid receptor. Proc. Natl. Acad. Sci. U.S.A. 91: 6069-6073, 1994.
6. COULTER, D. A., HUGENARD, J. R. AND PRINCE, D. A.: Characterization of ethosuximide reduction of low-threshold calcium current in thalamic neurons. Ann. Neurol. 25: 582-593, 1989.
7. CRAIG, C. R.: Anticonvulsant activity of steroids: Separability of anticonvulsant from hormonal effects. J. Pharmacol. Exp. Ther. 153: 337-343, 1966.
8. DAM, M., GRAM, L., PHILBERT, A., HANSEN, B. S., BLATT-LYON, B., CHRISTIENSEN, J. M. AND ANGELO, H. R.: Progabide: A controlled trial in partial epilepsy. Epilepsia 24: 127-135, 1983.
9. DAM, M., REEH PETERSEN, H., JENSEN, I., GRAM, L., PHILBERT, A., STENSGAARD HANSEN, B., BLATT-LYON, B., MOLIN CHRISTENSEN, J. AND ANGELO, H. R.: GABA-agonists in the treatment of epilepsy. Acta Neurol. Scand. 65: suppl. 90, 191-192, 1982.
10. FARWELL, J. R., LEE, Y. J., HIRTZ, D. G., SULZBACHER, S. I., ELLENBERG, J. H. AND NELSON, K. B.: Phenobarbital for febrile seizures: Effects on intelligence and on seizure recurrence. N. Engl. J. Med. 322: 364-369, 1990.
11. GEE, K. W., BOLGER, M. B., BRINTON, R. E., COIRINI, H. AND MCEWEN, B. S.: Steroid modulation of the chloride ionophore in rat brain: Structure-activity requirements, regional dependence and mechanism of action. J. Pharmacol. Exp. Ther. 246: 803-812, 1988.
12. A receptor complex: The pharmacological properties and therapeutic potential of epalons. Crit. Rev. Neurobiol. 9: 207-277, 1995.
13. GLADDING, G. D., KUPFERBERG, H. J. AND SWINYARD, E. A.: Antiepileptic drug development program. In Antiepileptic Drugs, Handbook of Experimental Pharmacology, ed. by H. H. Frey and D. Janz, vol. 74, pp. 343-347, Springer-Verlag, Berlin, 1985.
14. A receptor complex in rat cortex. Eur. J. Pharmacol. 288: 157-162, 1995.
15. GRANT, S. M. AND HEEL, R. C.: Vigabatrin: A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in epilepsy and disorders of motor control. Drugs 41: 889-926, 1991.
16. A receptor complex. J. Pharmacol. Exp. Ther. 241: 346-353, 1987.
17. A receptor function. Mol. Pharmacol. 46: 977-985, 1994.
18. A receptor. Methods Neurosci. 33: 446-467, 1994.
19. HINT, H. C. AND RICHTER, A. W.: A simple intravenous infusion technique for mice: Method and some applications. Pharmacol. Toxicol. 14: 153-157, 1958
20. A receptor. J. Med. Chem. 40: 61-72, 1997.
21. HÖGSKILDE, S., WAGNER, J., CARL, P., ANKER, N., ANGELO, H. R. AND SORENSEN, M. B.: Anticonvulsive properties of pregnanolone emulsion compared with althesin and thiopentone. Br. J. Anaesth. 61: 462-467, 1988.
22. A receptors. Mol. Pharmacol. 37: 429-434, 1990.
23. KOKATE, T. G., SVENSSON, B. E. AND ROGAWSKI, M. A.: Anticonvulsant activity of neurosteroids: Correlation with γ-aminobutyric acid-evoked chloride current potentiation. J. Pharmacol. Exp. Ther. 270: 1223-1229, 1994.
24. LAMBERT, J. J., BELILLI, D., HILL-VENNING, C. AND PETERS, J. A.: Neurosteroids and GABAA receptor function. Trends Pharmacol. Sci. 16: 295-303, 1995.
25. LANDGREN, S., ASSLY, J., BACKSTROM, T., DUBROVSKY, B. AND DANIELSSON, E.: The effect of progesterone and its metabolites on the interictal epileptiform discharge in the cat's cerebral cortex. Acta Physiol. Scand. 131: 33-42, 1987.
26. LEPPIK, I. E., DREIFUSS, F. E., PORTER, R. J., BOWMAN, T., SANTILLI, N., JACOBS, M. K., CROSBY, C., CLOYD, J., STACKMAN, J., GRAVES, N., SUTULA, T., WELTY, T., VICKERY, J., BRUNDAGE, R., GATES, J. AND GUMNIT, R. J.: A controlled study of progabide in partial seizures: Methodology and results. Neurology 37: 963-968, 1987.
27. LITCHFIELD, J. T. AND WILCOXON, F.: A simplified method of evaluating dose-effect experiments. J. Pharmacol. Exp. Ther. 96: 99-105, 1949.
28. LOISEAU, P., HARDENBERG, J. P., PESTRE, M., GUYOT, M., SCHECTER, P. J. AND TELL, G. P.: Double-blind, placebo-controlled study of vigabatrin (gamma-vinyl GABA) in drug-resistant epilepsy. Epilepsia 27: 115-120, 1986.
29. LÖSCHER, W.: Relationship between drug-induced changes in seizure thresholds and the GABA content of brain and nerve endings. Naunyn-Schmiedeberg's Arch. Pharmacol. 317: 131-134, 1981a.
30. LÖSCHER, W.: Correlation between alterations in brain GABA metabolism and seizure excitability following administration of GABA aminotransferase inhibitors and valproic acid: A re-evaluation. Neurochem. Int. 3: 397-404. 1981b.
31. LÖSCHER, W.: GABA-mimetics in animal models of seizure states. In Epilepsy and GABA Receptor Agonists: Basic and Therapeutic Research, ed. by G. Bartholini, L. Bossi, K. G. Lloyd and P. L. Morselli, pp. 109-119, Raven Press, New York, 1985.
32. LÖSCHER, W., JÄCKEL, R. AND CZUCZWAR, S. J.: Is amygdala kindling in rats a model for drug-resistant partial epilepsy? Exp. Neurol. 93: 211-226, 1986.
33. LÖSCHER, W. AND SCHMIDT, D.: 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, 1988.
34. LÖSCHER, W. AND SCHMIDT, D.: Strategies in antiepileptic drug development: Is rational drug design superior to random screening and structural variation? Epilepsy Res. 17: 95-134, 1994.
35. A/benzodiazepine receptor heterogeneity: Neurophysiological implications. Neuropharmacology 34: 245-254, 1995.
36. MACDONALD, R. L. AND KELLY, K. M.: Antiepileptic drug mechanisms of action. Epilepsia 36: suppl. 2, S2-S12, 1995.
37. MAJEWSKA, M. D., HARRISON, J. L., SCHWARTZ, R. D., BARKER, J. L. AND PAUL, S. M.: Steroid hormone metabolites are barbiturate-like modulators of the GABA receptor. Science (Wash. DC) 232: 1004-1007, 1986.
38. MCCABE, R. T., WASTERLAIN, C. G., KUCHARCZYK, N., SOFIA, R. D. AND VOGEL, J. R.: Evidence for anticonvulsant and neuroprotectant action of felbamate mediated by strychnine-insensitive glycine receptors. J. Pharmacol. Exp. Ther. 264: 1248-1252, 1993.
39. MELDRUM, B. S.: GABA and other amino acids. In Antiepileptic Drugs, Handbook of Experimental Pharmacology, ed. by H. H. Frey and D. Janz, vol. 74, pp. 153-188, Springer-Verlag, Berlin, 1985.
40. MELDRUM, B. S. AND HORTON, R.: Effects of the bicyclic GABA agonist, THIP, on myoclonic and seizure responses in mice and baboons with reflex epilepsy. Eur. J. Pharmacol. 61: 231-237, 1980.
41. MENGEL, H.: Tiagabine. Epilepsia 35: suppl. 5, S81-S84, 1994.
42. MCNAMARA, J. O.: Kindling: An animal model of complex partial epilepsy. Ann. Neurol. 16: suppl., S72-S76, 1984.
43. MORROW, A. L., SUZDAK, P. D. AND PAUL, S. M.: Steroid hormone metabolites potentiate GABA receptor-mediated chloride ion flux with nanomolar potency. Eur. J. Pharmcol. 142: 483-485, 1987.
44. MYSOLOBODSKY, M. S., ACKERMANN, R. F. AND ENGEL, J., JR.: Effects of γ-acetylenic GABA and γ-vinyl GABA on metrazol-activated, and kindled seizures. Pharmacol. Biochem. Behav. 11: 265-271, 1979.
45. NICHOLL, R. A. AND WOJTOWICZ, J. M.: The effects of pentobarbital and related compounds on frog motoneurons. Brain Res. 191: 225-237, 1980.
46. NIELSEN, E. B., SUZDAK, P. D., ANDERSEN, K. E., KNUTSEN, L. J. S., SONNKWALD, U. AND BRAEBTRUP, C.: Characterization of tiagabine (NO-328), a new potent selective GABA uptake inhibitor. Eur. J. Pharmacol. 196: 257-266, 1991.
47. ORLOF, M. J., WILLIAMS, H. L. AND PFEIFFER, C. C.: Timed intravenous infusion of metrazol and strychnine for testing anticonvulsant drugs. Proc. Soc. Exp. Biol. Med. 70: 254-257, 1949.
48. PALFREYMAN, M. G., SCECHTER, P. J., BUCKETT, W. R., TELL, G. P. AND KOCHWESER, J.: The pharmacology of GABA-transaminase inhibitors. Biochem. Pharmacol. 30: 817-824, 1981.
49. A receptor by depressant barbiturates and pregnane steroids. Br. J. Pharmacol. 94: 1257-1269, 1988.
50. PETERSON, S. L.: Anticonvulsant profile of an anesthetic steroid. Neuropharmacology 28: 877-879, 1989.
51. PHILLIPPS, G. H.: Structure-activity relationships in steroidal anaesthetics. J. Steroid Biochem. 6: 606-613, 1975.
52. RACINE, R. J.: Modification of seizure activity by electrical stimulations. II. Motor seizure. Electroenceph. Clin. Neurophysiol. 32: 281-294, 1972.
53. ROGAWSKI, M. A. AND PORTER, R. J.: Antiepileptic drugs and pharmacological mechanisms and clinical efficacy with consideration of promising developmental stage compounds. Pharmacol. Rev. 42: 223-286, 1990.
54. SATO, S.: Benzodiazepines: Clonazepam. In Antiepileptic Drugs, ed. by R. Levy, R. Mattson, B. Meldrum, J. K. Penry and F. E. Dreifuss, ed. 3, pp. 765-784, Raven Press, New York, 1989.
55. SATZINGER, G.: Antiepileptics from gamma-aminobutyric acid. Arzneim.-Forsch. 44: 261-266, 1994.
56. SCHACHTER, S. C.: Tiagabine monotherapy in the treatment of partial epilepsy. Epilepsia 36: suppl. 6, S2-S6, 1995.
57. SCHMIDT, D.: Benzodiazepines: Diazepam. In Antiepileptic Drugs, ed. by R. Levy, R. Mattson, B. Meldrum, J. K. Penry and F. E. Dreifuss, ed. 3, pp. 735-764, Raven Press, New York, 1989.
58. SCHMIDT, D. AND UTECH, K.: Progabide for refractory partial epilepsy: A controlled add-on trial. Neurology 36: 217-221, 1986.
59. SEDMAN, A. J., GILMET, G. P., SAYED, A. J. AND POSVAR, E. L.: Initial human safety and tolerance study of a GABA uptake inhibitor, CI-966: Potential role of GABA as a mediator in the pathogenesis of schizophrenia and mania. Drug Dev. Res. 21: 235-242, 1990.
60. SEYLE, H.: The antagonism between anesthetic steroid hormones and pentamethylenetetrazol (metrazol). J. Lab. Clin. Med. 27: 1051-1053, 1942.
61. SHETII, R. D., BUCKLEY, D., PENNEY, S. AND HOBBS, G. R.: Vigabatrin in childhood epilepsy: Comparable efficacy for generalized and partial seizures. Clin. Neuropharmacol. 19: 297-304, 1996.
62. SHULZ, D. W. AND MACDONALD, R. L.: Barbiturate enhancement of GABA-mediated inhibition and activation of chloride channel conductance: Correlation with anticonvulsant and anaesthetic actions. Brain Res. 209: 177-188, 1981.
63. SMITH, S. E., PARVEZ, N. S., CHAPMAN, A. G. AND MELDRUM, B. S.: The γ-aminobutyric acid uptake inhibitor, tiagabine, is anticonvulsant in two animal models of reflex epilepsy. Eur. J. Pharmacol. 273: 259-265, 1995.
64. STONE, W. E.: Systemic chemical convulsants and metabolic derangements. In Experimental Models of Epilepsy: A Manual for the Laboratory Worker, ed. by D. P. Purpura, J. K. Penry, D. B. Tower, D. M. Woodbury and R. D. Walker, pp. 407-432, Raven Press, New York, 1972.
65. SUBRAMANIAM, S., RHO, J. M., PENIX, L., DONEVAN, S. D., FIELDING, R. P. AND ROGAWSKI, M. A.: Felbamate block of the N-methyl-D-aspartate receptor. J. Pharmacol. Exp. Ther. 273: 878-886, 1995.
66. SWINYARD, E. A.: Assay of antiepileptic drug activity in experimental animals: Standard tests. In Anticonvulsant Drugs, International Encyclopedia of Pharmacology and Therapeutics, ed. by J. Mercier, sect. 19, vol. 1, pp. 47-65, Raven Press, New York, 1972.
67. SWINYARD, E. A., SOFIA, R. D. AND KUPFERBERG, H. J.: Comparative anticonvulsant activity and neurotoxicity of felbamate and four prototype antiepileptic drugs in mice and rats. Epilepsia 27: 27-34, 1986.
68. SWINYARD, A. E., WOLF, H. H., WHITE, H. S., SKEEN, G. A., STARK, L. G., ALBERTSON, T., PONG, S. F. AND DRUST, E. G.: Characterization of the anticonvulsant properties of F-721. Epilepsy Res. 15: 35-45, 1993.
69. SWINYARD, A. E. AND WOODHEAD, J. H.: Experimental detection, quantification and evaluation of anticonvulsants. In Antiepileptic Drugs, ed. by D. M. Woodbury, J. K. Penry and R. P. Schmidt, pp. 111-126, Raven Press, New York, 1982.
70. 3H]dihydropicrotoxinin binding sites at the benzodiazepine-GABA receptor-ionophore complex. Brain Res. 223: 218-222, 1981.
71. TURNER, D.M., RANSOM, R. W., YANG, S.-J. AND OLSEN, R. W.: Steroid anesthetics and naturally occurring analogs modulate the γ-aminobutyric acid receptor complex at a site distinct from barbiturates. J. Pharmacol. Exp. Ther. 248: 960-966, 1989.
72. VINING, E. P. G., MELLITIS, E. D., DORSEN, M. M, CATALDO, M. F., QUASKEY, S. A., SPIELBERG, S. P. AND FREEMAN, J. M.: Psychologic and behavioral effects of antiepileptic drugs in children: A double-blind comparison between phenobarbital and valproic acid. Pediatrics 80: 165-174, 1987.
73. WHITE, H. S.: New mechanisms of antiepileptic drugs. In Epilepsies II, ed. by R. Porter and D. Chadwick, pp. 1-30, Butterworth Heinemann, Boston, 1997.
74. WHITE, H. S., HARMSWORTH, W. L., SOFIA, R. D. AND WOLF, H. H.: Felbamate modulates the strychnine-sensitive glycine receptor. Epilepsy Res. 20: 41-48, 1995.
75. WIELAND, S., BELLUZI, J. D., STEIN, L. AND LAN, N. C.: Comparative behavioral characterization of the neuroactive steroids 3α-OH,5α-pregnan-20-one and 3α-OH,5β-pregnan-20-one in rodents. Psychopharmacology 118: 65-71, 1995.
76. + RNA from mammalian brain and retina. J. Pharmacol. Exp. Ther. 41: 89-103, 1992.
77. WORMS, P., DEPOORTERE, H., DURAND, A., MORSELLI, P. L., LLOYD, K. G. AND BARTOLINI, G.: γ-Aminobutyric acid (GABA) receptor stimulation. I. Neuropharmacological profiles of progabide (SL 76002) and SL 75102, with emphasis on their anticonvulsant spectrum. J. Pharmacol. Exp. Ther. 220: 660-671, 1982.