Synthesis and Evaluation of a Series of 2-Substituted-5-Thiopropylpiperazine (Piperidine)-1,3,4-Oxadiazoles Derivatives as Atypical Antipsychotics

Background: It is important to develop novel antipsychotics that can effectively treat schizophrenia with minor side-effects. The aim of our work is to develop novel antipsychotics that act on dopamine D-2 and D-3, serotonin 5-HT1A and 5-HT2A receptors with low affinity for the serotonin 5-HT2C and H-1 receptors, which can effectively cure positive symptoms, negative symptoms and cognitive impairment without the weight gain side-effect. Methodology/Principal Findings: A series of 2-substituted-5-thiopropylpiperazine (piperidine) -1,3,4-oxadiazoles derivatives have been synthesized and the target compounds were evaluated for binding affinities to D-2, 5-HT1A and 5-HT2A receptors. Preliminary results indicated that compounds 14, 16 and 22 exhibited high affinities to D-2, 5-HT1A and 5-HT2A receptors among these compounds. Further binding tests showed that compound 22 had high affinity for D-3 receptor, and low affinity for serotonin 5-HT2C and H-1 receptors. In addition, compound 22 inhibited apomorphine-induced climbing behavior and MK-801-induced hyperactivity with no extrapyramidal symptoms liability in mice. Moreover, compound 22 exhibited acceptable pharmacokinetic properties. Conclusions/Significance: Compound 22 showed an atypical antipsychotic activity without liability for extrapyramidal symptoms. We anticipate compound 22 to be useful for developing a novel class of drug for the treatment of schizophrenia.