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Vol. 280, Issue 3, 1284-1295, 1997
-Hydroxy-3
-methyl-5-pregnan-20-one), a Selective,
High-Affinity, Steroid Modulator of the 
-Aminobutyric
AcidA Receptor
Departments of
Pharmacology (R.B.C., P.L.W., S.W., J.E.H.) and
Medicinal Chemistry (S.M., S.H.T., N.C.L.), CoCensys,
Inc., Irvine, California;
Department of Pharmacology, University of
Dundee, Scotland (D.B., J.J.L.);
Anticonvulsant Screening Program,
Department of Pharmacology, University of Utah, Salt Lake City, Utah
(H.S.W., H.H.W.);
School of Pharmacy, University of Southern
California, Los Angeles, California (M.B.B.); and
Department of
Pharmacology, College of Medicine, University of California, Irvine,
California (K.W.G.)
Ganaxolone (CCD 1042) is a 3
-methyl-substituted analog of the
endogenous neuroactive steroid 3
-hydroxy-5-pregnan-20-one. Ganaxolone inhibited binding of the 
-aminobutyric acid
(GABA)A receptor-chloride channel ligand
t-[35S]butylbicyclophosphorothionate
(IC50 of 80 nM) and enhanced binding of the benzodiazepine
site ligand [3H]flunitrazepam (EC50 of 125 nM) and the GABA site ligand [3H]muscimol
(EC50 of 86 nM), consistent with activity as a positive allosteric modulator of the GABAA receptor.
Electrophysiological recordings showed that, whereas nanomolar
concentrations of ganaxolone potentiated GABA-evoked chloride currents
in Xenopus oocytes expressing the human
GABAA receptor subunits 112L,
212L or 312L, direct
activation of chloride flux occurred to a limited extent only at
micromolar concentrations. Ganaxolone was effective in nontoxic doses
against clonic convulsions induced by s.c. pentylenetetrazol administration in mice and rats (ED50 values of 4.3 and 7.8 mg/kg i.p., respectively). Ganaxolone also exhibited potent
anticonvulsant activity against seizures induced by s.c. bicuculline
(ED50 of 4.6 mg/kg i.p.), i.p. TBPS (ED50 of
11.7 mg/kg i.p.) and i.p. aminophylline (ED50 of 11.5 mg/kg
i.p.) in mice. Although ganaxolone effectively blocked tonic seizures
induced by maximal electroshock in mice (ED50 of 29.7 mg/kg
i.p.), it did so only at doses that produced ataxia on the Rotorod
(TD50 of 33.4 mg/kg i.p.). Conversely, ganaxolone was a
potent anticonvulsant against fully kindled stage 5 seizures induced by
corneal kindling in rats (ED50 of 4.5 mg/kg i.p.),
producing these effects at doses well below those that resulted in
ataxia (TD50 of 14.2 mg/kg i.p.). The seizure threshold, as
determined by an increase in the dose of i.v. infused pentylenetetrazol required to induce clonus, was also significantly elevated by nontoxic
doses of ganaxolone in mice. In summary, these data indicate that
ganaxolone is a high-affinity, stereoselective, positive allosteric
modulator of the GABAA receptor complex that exhibits potent anticonvulsant activity across a range of animal procedures. The
profile of anticonvulsant activity obtained for ganaxolone supports
clinical evaluation of this drug as an antiepileptic therapy with
potential utility in the treatment of generalized absence seizures as
well as simple and complex partial seizures.
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