Synthesis and Biological Evaluation of Fused Tricyclic Heterocycle Piperazine (Piperidine) Derivatives As Potential Multireceptor Atypical Antipsychotics

Herein,
a novel series of multireceptor ligands was developed as
polypharmacological antipsychotic agents using the designed multiple
ligand approach between dopamine receptors and serotonin receptors.
Among them, compound 47 possessed unique pharmacological
features, exhibiting high affinities for D2, D3, 5-HT1A, 5-HT2A, and 5-HT6 receptors
and low efficacy at the off-target receptors (5-HT2C, histamine
H1, and adrenergic α1 receptor). Compound 47 showed dose-dependent inhibition of apomorphine- and MK-801-induced
motor behavior, and the conditioned avoidance response with low cataleptic
effect. Moreover, compound 47 resulted nonsignificantly
serum prolactin levels and weight gain change compared with risperidone.
Additionally, compound 47 possessed a favorable pharmacokinetic
profile with oral bioavailability of 58.8% in rats. Furthermore, compound 47 displayed procognition properties in a novel object recognition
task in rats. Taken together, compound 47 may constitute
a novel class of atypical antipsychotic drugs for schizophrenia.