osu-6162 and Schizophrenia

The first part of the present review describes the exciting journey of dopamine stabilizers, starting in the early eighties with the development of the partial dopamine agonist (-)-3-PPP of phenylpiperidine structure, via various compounds with aminotetraline structure with preferential autoreceptor antagonist properties, and then back again to phenylpiperidine compounds carrying substituents on the aromatic ring that transformed them from partial dopamine agonists to partial dopamine receptor antagonists, such as OSU6162. OSU6162 was brought to the clinic and has in preliminary trials showed antidyskinetic and antipsychotic efficacy. The second part of this review describes results from a hypoglutamatergia mouse model for cognitive symptoms of schizophrenia, where we have tested traditional neuroleptics, new generation antipsychotics with marked 5-HT2 vs dopamine D2 receptor blockade as well as a dopamine stabilizer belonging to the partial dopamine receptor antagonist category.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Disease Models, Animal; Dopamine; Dopamine Agonists; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Glutamic Acid; Mice; Piperazines; Piperidines; Quinolones; Schizophrenia

The early demonstration of chlorpromazine efficacy in schizophrenia and its subsequent identification as a dopamine receptor antagonist, established the only known mechanism for antipsychotic development to date. By extension, it is easy to hypothesize that any mechanism shown to reduce dopamine-mediated transmission in brain will have antipsychotic properties. The evaluation of partial dopamine agonists for antipsychotic efficacy and their application in the treatment of psychosis has derived from this background. Partial dopamine agonists at the D2 dopamine receptor, have high affinity for that receptor, but reduced intrinsic activity. These agonists have higher affinity for the presynaptic autoreceptor than for the postsynaptic receptor. Hence, these compounds reduce dopamine synthesis and release through an agonist action at the dopamine autoreceptor. Moreover, the agonists have lower intrinsic activity at the postsynaptic receptor than its natural ligand dopamine. Therefore, they diminish the dopaminergic signal at postsynaptic sites as well through delivering a reduced message; this component of drug action becomes more prominent the lower the intrinsic activity of the drug. Several partial dopamine agonists have been evaluated in schizophrenia. One of them, aripiprazole, is nearing approval for marketing. With partial dopamine agonist treatment, advantages should accrue to schizophrenia treatment in the areas of affect control and cognitive performance.

Topics: Animals; Dopamine Agonists; Humans; Piperidines; Psychotic Disorders; Receptors, Dopamine; Schizophrenia

The monoamine stabilizer (3S)-3-[3-(methenesulfonyl)phenyl]-1-propylpiperidine hidrochloride [(-)-OSU6162] is a promising compound for the treatment of neurological and psychiatric disorders, such as schizophrenia. Here, we tested the hypothesis that (-)-OSU6162 prevents hyperlocomotion and sensorimotor deficits in prepulse inhibition of the startle response (PPI) induced by psychomimetic drugs. Male Swiss mice received injections of (-)-OSU6162 (1, 3, 10, or 30 mg/kg), and their motor responses were investigated in the open field and in the catalepsy tests, which predicts liability to induce sedation and extrapyramidal side effects, respectively. Next, in independent experiments, this compound was evaluated for its efficacy to prevent hyperlocomotion induced by cocaine (10 mg/kg; dopamine transporter inhibitor) or ketamine (60 mg/kg; glutamate NMDA channel blocker) in the open field. Finally, we tested if (-)-OSU6162 prevents PPI disruption induced by MK-801 (0.5 mg/kg; glutamate NMDA channel blocker). (-)-OSU6162 induced neither locomotion impairment nor catalepsy. This compound prevented cocaine-induced hyperlocomotion at the doses of 10 and 30 mg/kg and ketamine-induced hyperlocomotion at the doses of 1 and 3 mg/kg. In the sensorimotor test, (-)-OSU6162 failed to reverse MK-801-induced PPI deficits. The dopamine stabilizer (-)-OSU6162 prevents the hyperactivity induced by dopaminergic and anti-glutamatergic drugs at doses that preserve motor functions, although it failed in the PPI test. Its therapeutic potential for specific symptoms of schizophrenia warrants further investigation in both preclinical and clinical studies.

Topics: Animals; Antipsychotic Agents; Behavior, Animal; Cocaine; Dopamine Uptake Inhibitors; Excitatory Amino Acid Antagonists; Ketamine; Locomotion; Male; Mice; Piperidines; Receptors, N-Methyl-D-Aspartate; Reflex, Startle; Schizophrenia