Synthesis and Biological Investigation of Coumarin Piperazine (Piperidine) Derivatives as Potential Multireceptor Atypical Antipsychotics

The discovery and synthesis of potential and novel antipsychotic coumarin derivatives, associated with potent dopamine D₂, D₃, and serotonin 5-HT_1A and 5-HT_2A 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 D₂ and D₃ and serotonin 5-HT_1A and 5-HT_2A receptors. Moreover, it possesses low affinity for 5-HT_2C and H₁ 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