CHARACTERIZATION OF THE ANTICONVULSANT PROPERTIES OF GANAXOLONE (CCD 1042, PHA-HYDROXY-3-BETA-METHYL-5-ALPHA-PREGNAN-20-ONE), A SELECTIVE, HIGH-AFFINITY, STEROID MODULATOR OF THE GAMMA-AMINOBUTYRIC ACID(A) RECEPTOR

Ganaxolone (CCD 1042) is a 3 beta-methyl-substituted analog of the end ogenous neuroactive steroid 3 alpha-hydroxy-5 alpha-pregnan-20-one. Ga naxolone inhibited binding of the gamma-aminobutyric acid (GABA)(A) re ceptor-chloride channel ligand t-[S-35]butylbicyclophosphorothionate ( IC50 of 80 nM) and enhanced binding of the benzodiazepine site ligand [H-3]flunitrazepam (EC(50) of 125 nM) and the GABA site ligand [H-3]mu scimol (EC(50) of 86 nM), consistent with activity as a positive allos teric modulator of the GABA(A) receptor. Electrophysiological recordin gs showed that, whereas nanomolar concentrations of ganaxolone potenti ated GABA-evoked chloride currents in Xenopus oocytes expressing the h uman GABA(A) receptor subunits alpha 1 beta 1 gamma 2(L), alpha 2 beta 1 gamma 2(L) or alpha 3 beta 1 gamma 2(L), direct activation of chlor ide flux occurred to a limited extent only at micromolar concentration s. Ganaxolone was effective in nontoxic doses against clonic convulsio ns induced by s.c. pentylenetetrazol administration in mice and rats ( ED(50) values of 4.3 and 7.8 mg/kg i.p., respectively). Ganaxolone als o exhibited potent anticonvulsant activity against seizures induced by s.c. bicuculline (ED(50) of 4.6 mg/kg i.p.), i.p. TBPS (ED(50) of 11. 7 mg/kg i.p.) and i.p. aminophylline (ED(50) of 11.5 mg/kg i.p.) in mi ce. Although ganaxolone effectively blocked tonic seizures induced by maximal electroshock in mice (ED(50) of 29.7 mg/kg i.p.), it did so on ly at doses that produced ataxia on the Rotorod (TD50 of 33.3 mg/kg i. p.). Conversely, ganaxolone was a potent anticonvulsant against fully kindled stage 5 seizures induced by corneal kindling in rats (ED(50) o f 4.5 mg/kg i.p.), producing these effects at doses well below those t hat resulted in ataxia (TD50 of 14.2 mg/kg i.p.). The seizure threshol d, as determined by an increase in the dose of i.v. infused pentylenet etrazol 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 alloster ic modulator of the GABA(A) receptor complex that exhibits potent anti convulsant activity across a range of animal procedures. The profile o f anticonvulsant activity obtained for ganaxolone supports clinical ev aluation of this drug as an antiepileptic therapy with potential utili ty in the treatment of generalized absence seizures as well as simple and complex partial seizures.