WAY-163909, a 5-HT2C agonist, enhances the preclinical potency of current antipsychotics.

Abstract

INTRODUCTION:

5-HT(2C) agonists, by decreasing mesolimbic dopamine without affecting nigrostriatal dopamine, are predicted to have antipsychotic efficacy with low extrapyramidal side effects (EPS). Combining 5-HT(2C) agonists with low doses of existing antipsychotics could increase treatment efficacy while reducing treatment liabilities such as EPS (typical antipsychotics), and the propensity for weight gain (atypical antipsychotics).

OBJECTIVES:

The objectives of these studies were to combine WAY-163909, a selective 5-HT(2C) agonist, with either the typical antipsychotic haloperidol, or the atypical antipsychotic clozapine, at doses that were ineffective on their own, with the expectation that a shift in potency in several rodent behavior models predictive of antipsychotic activity would occur.

RESULTS AND DISCUSSION:

In mice, co-administration of either haloperidol, or clozapine, produced a significant leftward shift in the ability of WAY-163909 to block apomorphine-induced climbing behavior, without any affect on apomorphine-induced stereotypy or an increased propensity for catalepsy. In the rat-conditioned avoidance model, WAY-163909 was combined with either haloperidol or clozapine at doses that individually produced reductions in avoidance response on the order of 10%, while the combination of WAY-163909 and either of the antipsychotics resulted in a greater than 70% reduction in avoidance, with no evidence of response failures, or pharmacokinetic interaction.

CONCLUSION:

Doses of either haloperidol or clozapine, that failed to antagonize an MK-801 induced deficit in prepulse inhibition, significantly attenuated the sensory gating deficit when combined with WAY-163909. Data support the notion that 5-HT(2C) receptor agonists, co-administered with other marketed antipsychotics, allow for dose sparing with a more favorable side-effect profile.

• Authors: Steven M Grauer, Radka Graf, Rachel Navarra, Amy Sung, Sheree F Logue, Gary Stack, Christine Huselton, Zhi Liu, Thomas A Comery, Karen L Marquis, Sharon Rosenzweig-Lipson
• Journal: Psychopharmacology (Psychopharmacology (Berl)) Vol. 204 Issue 1 Pg. 37-48 (May 2009) ISSN: 1432-2072 [Electronic] Germany
• PMID: 19107466 (Publication Type: Journal Article)

Chemical References

• 1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta(b)(1,4)diazepino(6,7,1hj)indole
• Antipsychotic Agents
• Azepines
• Indoles
• Serotonin 5-HT2 Receptor Agonists
• Dizocilpine Maleate
• Clozapine
• Haloperidol
• Apomorphine

Topics

• Animals
• Antipsychotic Agents (adverse effects, pharmacology, therapeutic use)
• Apomorphine (antagonists & inhibitors)
• Avoidance Learning (drug effects)
• Azepines (adverse effects, pharmacology, therapeutic use)
• Catalepsy (chemically induced, drug therapy)
• Clozapine (adverse effects, pharmacology, therapeutic use)
• Dizocilpine Maleate (pharmacology)
• Drug Synergism
• Drug Therapy, Combination
• Haloperidol (adverse effects, pharmacology, therapeutic use)
• Indoles (adverse effects, pharmacology, therapeutic use)
• Male
• Mice
• Rats
• Rats, Sprague-Dawley
• Reflex, Startle (drug effects)
• Serotonin 5-HT2 Receptor Agonists
• Stereotyped Behavior (drug effects)