Synthesis and biological evaluation of new 6-hydroxypyridazinone benzisoxazoles: Potential multi-receptor-targeting atypical antipsychotics.

Abstract In recent years, multi-targeting directed ligands have attracted great interest as possible new atypical antipsychotics. Combinations of dopamine and serotonin receptor ligands within single molecules might afford new therapeutic opportunities. Herein, we describe the synthesis of a novel series of 6-hydroxypyridazinone benzisoxazoles and their binding behaviors to different receptors in terms of atypical antipsychotic behaviors. The most potent compound (46) exhibited excellent affinities for certain receptors (D 2 , K i  = 0.5 ± 0.07 nM; 5-HT 1A , K i  = 5.9 ± 0.8 nM; 5-HT 2A , K i  = 0.3 ± 0.01 nM; 5-HT 6 , K i  = 0.5 ± 0.04 nM) and combined with low affinities for the H 1 , 5-HT 2C , and adrenergic α 1 receptors. In contrast to risperidone, compound 46 exhibited a high cataleptic threshold; this may be useful in the development of a novel class of drugs treating schizophrenia.