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


OBJECTIVE
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.


CONCLUSIONS
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.


CONCLUSIONS
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.
Grauer
Steven M
SM
Discovery Neuroscience, Wyeth Research, CN 8000, Princeton, NJ 08543, USA. grauers@wyeth.com
Graf
Radka
R
Navarra
Rachel
R
Sung
Amy
A
Logue
Sheree F
SF
Stack
Gary
G
Huselton
Christine
C
Liu
Zhi
Z
Comery
Thomas A
TA
Marquis
Karen L
KL
Rosenzweig-Lipson
Sharon
S
D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D001058:Apomorphine / Q000037:antagonists & inhibitors; D001362:Avoidance Learning / Q000187:drug effects*; D001381:Azepines / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy; D003024:Clozapine / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D016291:Dizocilpine Maleate / Q000494:pharmacology; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D006220:Haloperidol / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D007211:Indoles / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051379:Mice; D051381:Rats; D017207:Rats, Sprague-Dawley; D013216:Reflex, Startle / Q000187:drug effects; D058826:Serotonin 5-HT2 Receptor Agonists; D013239:Stereotyped Behavior / Q000187:drug effects
C501656:1,2,3,4,8,9,10,10a-octahydro-7bH-cyclopenta(b)(1,4)diazepino(6,7,1hj)indole; D014150:Antipsychotic Agents; D001381:Azepines; D007211:Indoles; D058826:Serotonin 5-HT2 Receptor Agonists; D016291:Dizocilpine Maleate; D003024:Clozapine; D006220:Haloperidol; D001058:Apomorphine