Synthesis
and Biological Investigation of Coumarin
Piperazine (Piperidine) Derivatives as Potential Multireceptor Atypical
Antipsychotics
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Abstract
The
discovery and synthesis of potential and novel antipsychotic
coumarin derivatives, associated with potent dopamine D<sub>2</sub>, D<sub>3</sub>, and serotonin 5-HT<sub>1A</sub> and 5-HT<sub>2A</sub> receptor properties, are the focus of the present article. The most-promising
derivative was 7-(4-(4-(6-fluorobenzo[<i>d</i>]isoxazol-3-yl)-piperidin-1-yl)butoxy)-4-methyl-8-chloro-2<i>H</i>-chromen-2-one (<b>17m</b>). This derivative possesses
unique pharmacological features, including high affinity for dopamine
D<sub>2</sub> and D<sub>3</sub> and serotonin 5-HT<sub>1A</sub> and
5-HT<sub>2A</sub> receptors. Moreover, it possesses low affinity for
5-HT<sub>2C</sub> and H<sub>1</sub> receptors (to reduce the risk
of obesity associated with chronic treatment) and hERG channels (to
reduce the incidence of torsade des pointes). In animal models, compound <b>17m</b> inhibited apomorphine-induced climbing behavior, MK-801-induced
hyperactivity, and the conditioned avoidance response without observable
catalepsy at the highest dose tested. Further, fewer preclinical adverse
events were noted with <b>17m</b> compared with risperidone
in assays that measured prolactin secretion and weight gain. Acceptable
pharmacokinetic properties were also noted with <b>17m</b>.
Taken together, <b>17m</b> may constitute a novel class of drugs
for the treatment of schizophrenia