1192U90 in animal tests that predict antipsychotic efficacy, anxiolysis, and extrapyramidal side effects.
1192U90 was developed on the assumption that antagonism of 5-HT2 receptors efficacy yields more potently than D2 receptors against positive and negative symptoms of schizophrenia with minimal liability for extrapyramidal side effects (EPSs), and that 5-HT1A agonism further reduces EPSs and provides anxiolytic and antidepressant activity. 1192U90 was submitted to four tests that predict antipsychotic efficacy (antagonism of apomorphine-induced climbing in mouse, antagonism of apomorphine-induced circling in rats with unilateral 6-OHDA lesions, antagonism of amphetamine-induced hyperlocomotion in rat, and inhibition of conditioned avoidance in rat), two tests of 5-HT2 function (antagonism of 5-MeODMT-induced head twitches in mouse and antagonism of 5-HTP-induced wet dog shakes in rat), and three tests that predict EPS liability (antagonism of apomorphine-induced stereotypy in mouse and rat and induction of catalepsy in mouse). ED50s (mg/kg PO) were as follows: climbing 10.1, circling 7.9, hyperlocomotion 6.6, and avoidance 5.7; head twitches 5 and wet dog shakes 4.6; stereotypy in mouse 91.1, stereotypy in rat 133.4, and catalepsy 192.4. The ratio of ED50 for stereotypy antagonism to ED50 for climbing antagonism was 9 (compared to 4, 3, and 4 for clozapine, risperidone, and haloperidol). The ratio of ED50 for catalepsy induction to ED50 for climbing antagonism was 19 (compared to 7, 2, and 17 for clozapine, risperidone, and haloperidol). 1192U90 was also submitted to three tests that predict anxiolysis: It produced only a small increase in punished lever pressing for food in rat (Geller-Seifter conflict test), which is specific for rapid-onset efficacy, but produced large increases in punished key pecking for food in pigeon and cork gnawing in rat, which identify the delayed onset 5-HT1A agonists such as buspirone. The results suggest that 1192U90 would be effective for positive and negative symptoms of schizophrenia, with minimal liability for EPSs, and may also have anxiolytic properties.
Rigdon
G C
GC
Pharmacology and Molecular Therapeutics Division, Glaxo Wellcome, Inc., Research Triangle Park, NC 27709, USA.
Norman
M H
MH
Cooper
B R
BR
Howard
J L
JL
Boncek
V M
VM
Faison
W L
WL
Nanry
K P
KP
Pollard
G T
GT
D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects*; D010856:Columbidae; D008297:Male; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012559:Schizophrenia / Q000503:physiopathology*; D013844:Thiazoles / Q000494:pharmacology*
D014150:Antipsychotic Agents; D010879:Piperazines; D013844:Thiazoles; C098658:1192U90