CP-809,101, a selective 5-HT2C agonist, shows activity in animal models of antipsychotic activity.
CP-809,101 is a potent, functionally selective 5-HT(2C) agonist that displays approximately 100% efficacy in vitro. The aim of the present studies was to assess the efficacy of a selective 5-HT(2C) agonist in animal models predictive of antipsychotic-like efficacy and side-effect liability. Similar to currently available antipsychotic drugs, CP-809,101 dose-dependently inhibited conditioned avoidance responding (CAR, ED(50)=4.8 mg/kg, sc). The efficacy of CP-809,101 in CAR was completely antagonized by the concurrent administration of the 5-HT(2C) receptor antagonist, SB-224,282. CP-809,101 antagonized both PCP- and d-amphetamine-induced hyperactivity with ED(50) values of 2.4 and 2.9 mg/kg (sc), respectively and also reversed an apomorphine induced-deficit in prepulse inhibition. At doses up to 56 mg/kg, CP-809,101 did not produce catalepsy. Thus, the present results demonstrate that the 5-HT(2C) agonist, CP-809,101, has a pharmacological profile similar to that of the atypical antipsychotics with low extrapyramidal symptom liability. CP-809,101 was inactive in two animal models of antidepressant-like activity, the forced swim test and learned helplessness. However, CP-809,101 was active in novel object recognition, an animal model of cognitive function. These data suggest that 5-HT(2C) agonists may be a novel approach in the treatment of psychosis as well as for the improvement of cognitive dysfunction associated with schizophrenia.
Siuciak
Judith A
JA
CNS Discovery, Pfizer Global Research and Development, Eastern Point Road, Groton, CT 06340, USA. judith.a.siuciak@pfizer.com
Chapin
Douglas S
DS
McCarthy
Sheryl A
SA
Guanowsky
Victor
V
Brown
Janice
J
Chiang
Phoebe
P
Marala
Ravi
R
Patterson
Terrell
T
Seymour
Patricia A
PA
Swick
Andrew
A
Iredale
Philip A
PA
D000662:Amphetamines; D000818:Animals; D014150:Antipsychotic Agents / Q000737:chemistry / Q000627:therapeutic use*; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal; D002375:Catalepsy / Q000139:chemically induced / Q000188:drug therapy; D003913:Dextroamphetamine; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005106:Exploratory Behavior / Q000187:drug effects; D006380:Helplessness, Learned; D006801:Humans; D006948:Hyperkinesis / Q000139:chemically induced / Q000188:drug therapy; D007266:Inhibition, Psychological; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D041681:NIH 3T3 Cells; D010879:Piperazines / Q000737:chemistry / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D011618:Psychotic Disorders / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D011719:Pyrazines / Q000737:chemistry / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D044405:Receptor, Serotonin, 5-HT2C / Q000502:physiology; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000627:therapeutic use*
D000662:Amphetamines; D014150:Antipsychotic Agents; C518685:CP-809,101; D010879:Piperazines; D011719:Pyrazines; D044405:Receptor, Serotonin, 5-HT2C; D058826:Serotonin 5-HT2 Receptor Agonists; D017366:Serotonin Receptor Agonists; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine; D003913:Dextroamphetamine