Effects of BMY 14802, a potential antipsychotic drug, on rat brain dopaminergic function.
The potential neuroleptic alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine-butanol HCl (BMY 14802-1) was tested for its effects on mesotelencephalic dopamine (DA) neurons in albino rats. BMY 14802-1 increased DA turnover in DA terminal regions, increased nigral DA neuronal impulse flow and blocked the behavioral stimulation and inhibition of DA neuronal impulse flow caused by DA agonists. BMY 14802-1 also increased tyrosine hydroxylase activity in vivo but did not directly affect tyrosine hydroxylase activity in vitro. In contrast to these findings, BMY 14802-1 did not cause catalepsy at any dose and reversed catalepsy produced by haloperidol. BMY 14802-1 did not block DA autoreceptors on either DA neuron soma/dendrites or on striatal nerve terminals, as assessed by inhibition of DA neuronal impulse flow by microiontophoresed DA and by inhibition of tyrosine hydroxylase activity by apomorphine, respectively. BMY 14802-1 had very low affinity for striatal D-2 receptors (IC50 greater than 10(-5) M) as determined by displacement of [3H]spiperone binding in vitro. Finally, BMY 14802-1 increased impulse flow of nigral DA neurons after pretreatment with haloperidol but had no effect on impulse flow when microiontophoresed directly onto DA neurons. It is concluded that BMY 14802-1 blocked DA-mediated effects in the mesostriatal and mesocortical/limbic systems through a non-DA receptor mechanism. BMY 14802-1 has potential as a neuroleptic with little indication of extrapyramidal motor effects.
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects*; D002065:Buspirone; D004298:Dopamine / Q000502:physiology*; D005260:Female; D006220:Haloperidol / Q000494:pharmacology; D009474:Neurons / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D011954:Receptors, Dopamine / Q000378:metabolism; D013134:Spiperone / Q000378:metabolism; D013378:Substantia Nigra / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D014150:Antipsychotic Agents; D011743:Pyrimidines; D011954:Receptors, Dopamine; D015102:3,4-Dihydroxyphenylacetic Acid; C050408:alpha-(4-fluorophenyl)-4-(5-fluoro-2-pyrimidinyl)-1-piperazine butanol; D013134:Spiperone; D014446:Tyrosine 3-Monooxygenase; D006220:Haloperidol; D002065:Buspirone; D004298:Dopamine