govadine and Schizophrenia

New pharmacological treatments for the cognitive deficits in schizophrenia are needed. Tetrahydroprotoberberines, such as govadine, are one class of compounds with dopaminergic activities that may be useful in treating some aspects of the cognitive symptoms of the disorder.. The objective of the present studies was to test the effects of the D- and L-enantiomers of govadine on the impairment in a paired-associate learning (PAL) task produced by acute MK-801 in rats. We also assessed effects of the typical antipsychotic haloperidol as a comparator compound.. MK-801 (0.05, 0.1, 0.15, and 0.2 mg/kg), D- and L-govadine (0.3, 1.0, and 3.0 mg/kg), and haloperidol (0.05, 0.1, and 0.25 mg/kg) were administered acutely to rats well trained on the PAL task in touchscreen-equipped operant conditioning chambers.. Acute MK-801 impaired performance of PAL in a dose-dependent manner by reducing accuracy and increasing correction trials. L-Govadine (1.0 mg/kg), but not D-govadine, blocked the disruptive effects of MK-801 (0.15 mg/kg) on PAL. Haloperidol failed to affect the MK-801-induced disruption of PAL. Higher doses of L-govadine and haloperidol dramatically impaired performance of the task which confounded interpretation of cognitive outcomes.. L-Govadine appears unique in its ability to improve performance of the MK-801-induced impairment in the PAL task. This behavioral effect may relate the ability of L-govadine to antagonize dopamine D2 receptors while also promoting dopamine efflux. Future research should further characterize the role of the dopamine system in the rodent PAL task to elucidate the mechanisms of its pro-cognitive effects.

Topics: Animals; Antipsychotic Agents; Berberine Alkaloids; Conditioning, Operant; Dizocilpine Maleate; Dose-Response Relationship, Drug; Male; Paired-Associate Learning; Photic Stimulation; Rats; Rats, Long-Evans; Receptors, Dopamine D2; Schizophrenia

There is a pressing need to find and develop new antipsychotic agents for the treatment of schizophrenia. Current drugs primarily target dopamine D2 receptors and are only effective in the treatment of the positive symptoms of this indication. The tetrahydroprotoberberine natural product (±)-govadine has shown unique promise for the treatment of both the positive and negative symptoms of schizophrenia as it targets both dopamine D1 and D2 receptors. However, further clinical research has been hindered by the lack of availability of significant quantities of enantioenriched material. A new, enantioselective synthetic route has been developed that affords (-)-govadine in 39% overall yield over 5-steps from commercially available dopamine and homovanillic acid derivatives. Using only minor modifications in the synthetic route, (+)-govadine can be synthesized in comparable yields and enantioselectivities. The route is readily scalable as every intermediate was purified by crystallization and no flash column chromatography was necessary.

Topics: Antipsychotic Agents; Berberine Alkaloids; Cyclization; Drug Delivery Systems; Humans; Molecular Structure; Receptors, Dopamine D1; Receptors, Dopamine D2; Schizophrenia; Stereoisomerism