The extensive pharmacological evaluation of
JL 13 as an atypical
antipsychotic drug has revealed a close similarity to
clozapine, however with some major advantages.
JL 13 was characterized as a weak D(2) antagonist, both in vitro and in vivo, with a strong affinity for the D(4) and the 5-HT(2A) receptors. It has no affinity for the
5-HT(2C) receptor. In vivo microdialysis experiments in rat showed that
JL 13, like
clozapine, preferentially increased extracellular
dopamine concentrations in the prefrontal cortex compared to nucleus accumbens or striatum. Behavioral studies showed that
JL 13, like
clozapine, has the profile of an atypical
antipsychotic. Thus,
JL 13 did not antagonize
apomorphine-induced stereotypy nor did it produce
catalepsy, but it antagonized
apomorphine-induced climbing in rodents. It was inactive against
d-amphetamine-induced stereotypy but antagonized
d-amphetamine-induced hyperactivity in the mouse. Likewise, in the paw test, it was more effective in prolonging hindlimb retraction time than prolonging forelimb retraction time. Like other
antipsychotic drugs,
JL 13 reversed the
apomorphine- and
amphetamine-induced disruption of prepulse inhibition. In a complex temporal regulation schedule in the dog,
JL 13 showed a high resemblance with
clozapine without inducing
sialorrhea, palpebral ptosis or any significant motor side effects. In rats and squirrel monkeys
JL 13 induced a high degree of generalization (70%) to
clozapine. Regarding behavioral toxicology,
JL 13 did not produce
dystonia or Parkinsonian symptoms in
haloperidol-sensitized monkeys. After acute administration, again like
clozapine,
JL 13 induced only a transient increase in circulating
prolactin. Last but not the least, regarding a possible hematological toxicity, unlike
clozapine,
JL 13 did not present sensitivity to
peroxidase-induced oxidation. Moreover, its electrooxidation potential was close to that of
loxapine and far from that of
clozapine. Taking all these preclinical data into account, it appears that
JL 13 is a promising atypical
antipsychotic drug.