Multiple studies indicate that N-methyl-D-aspartate (NMDA) receptor hypofunction underlies some of the deficits associated with schizophrenia. One approach for improving NMDA receptor function is to enhance occupancy of the glycine modulatory site on the NMDA receptor by increasing the availability of the endogenous coagonists D-serine. Here, we characterized a novel D-amino acid oxidase (DAAO) inhibitor, compound 8 [4H-thieno [3,2-b]pyrrole-5-carboxylic acid] and compared it with D-serine. Compound 8 is a moderately potent inhibitor of human (IC 50 , 145 nM) and rat (IC 50 , 114 nM) DAAO in vitro. In rats, compound 8 (200 mg/kg) decreased kidney DAAO activity by ϳ96% and brain DAAO activity by ϳ80%. This marked decrease in DAAO activity resulted in a significant (p Ͻ 0.001) elevation in both plasma (220% of control) and cerebrospinal fluid (CSF; 175% of control) D-serine concentration. However, compound 8 failed to significantly influence amphetamine-induced psychomotor activity, nucleus accumbens dopamine release, or an MK-801 (dizocilpine maleate)-induced deficit in novel object recognition in rats. In contrast, high doses of D-serine attenuated both amphetamine-induced psychomotor activity and dopamine release and also improved performance in novel object recognition. Behaviorally efficacious doses of D-serine (1280 mg/kg) increased CSF levels of D-serine 40-fold above that achieved by the maximal dose of compound 8. These findings demonstrate that pharmacological inhibition of DAAO significantly increases D-serine concentration in the periphery and central nervous system. However, acute inhibition of DAAO appears not to be sufficient to increase D-serine to concentrations required to produce antipsychotic and cognitive enhancing effects similar to those observed after administration of high doses of exogenous D-serine.

Ganaxolone (GNX) is the 3b-methylated synthetic analog of the naturally occurring neurosteroid, allopregnanolone (ALLO). GNX is effective in a broad range of epilepsy and behavioral animal models and is currently in clinical trials designed to assess its anticonvulsant and antidepressant activities. The current studies were designed to broaden the anticonvulsant profile of GNX by evaluating its potential anticonvulsant activities following i.v. administration in treatment-resistant models of status epilepticus (SE), to establish a pharmacokinetic (PK)/pharmacodynamic (PD) relationship, and to compare its PK and anticonvulsant activities to ALLO. In PK studies, GNX had higher exposure levels, a longer halflife, slower clearance, and higher brain penetrance than ALLO. Both GNX and ALLO produced a sedating response as characterized by loss of righting reflex, but neither compound produced a full anesthetic response as animals still responded to painful stimuli. Consistent with their respective PK properties, the sedative effect of GNX was longer than that of ALLO. Unlike other nonanesthetizing anticonvulsant agents indicated for SE, both GNX and ALLO produced anticonvulsant activity in models of pharmacoresistant SE with administration delay times of up to 1 hour after seizure onset. Again, consistent with their respective PK properties, GNX produced a significantly longer anticonvulsant response. These studies show that GNX exhibited improved pharmacological characteristics versus other agents used as treatments for SE and position GNX as a uniquely acting treatment of this indication. These studies were supported by Marinus Pharmaceuticals, Inc.

No abstract