Increased release of dopamine in vivo by BMY-14802: contrasting pattern to clozapine.
In preclinical studies, BMY-14802 [alpha-(fluorophenyl)-4-(5-fluoro-2-pyramidinyl)-l-piperazine-buta nol], a potent sigma ligand, exhibited a profile similar to clozapine, an atypical antipsychotic agent. Several atypical antipsychotics have previously been demonstrated to increase dopamine (DA) metabolism without altering DA release in vivo, suggesting a potential mechanism for their lack of extrapyramidal side effects. BMY-14802 increased DA metabolism and release while clozapine increased DA metabolism but decreased DA release in the mouse. This is the first demonstration of a sigma ligand mediated DA release in vivo. The lack of extrapyramidal side effects, despite the enhanced DA release in vivo after BMY-14802 suggests that the atypical profile of clozapine can not be explained by its depressant actions on DA release alone.
Rao
T S
TS
CNS Diseases Research, G.D. Searle & Co., St. Louis, MO 63198.
Cler
J A
JA
Oei
E J
EJ
Iyengar
S
S
Wood
P L
PL
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001923:Brain Chemistry / Q000187:drug effects; D003024:Clozapine / Q000494:pharmacology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D003984:Dibenzazepines / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D006719:Homovanillic Acid / Q000378:metabolism; D008297:Male; D008781:Methyltyrosines / Q000378:metabolism; D051379:Mice; D009830:Olfactory Bulb / Q000187:drug effects / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D019805:alpha-Methyltyrosine
D014151:Anti-Anxiety Agents; D003984:Dibenzazepines; D008781:Methyltyrosines; D011743:Pyrimidines; D015102:3,4-Dihydroxyphenylacetic Acid; C050408:alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol; D019805:alpha-Methyltyrosine; D003024:Clozapine; D004298:Dopamine; D006719:Homovanillic Acid