Design, Synthesis And Biological Evaluation Of The Novel Multireceptor Antipsychotics

Schizophrenia is a severe mental illness that affects around 1% of the general population. Currently schizophrenia is usually treated with atypical antipsychotics. A major advantage of atypical antipsychotics is their effectiveness in suppressing positive and negative symptoms. However, it has proved that atypical antipsychotics cause numerous side effects, such as substantial weight gain and QT interval prolongation. The discovery of multireceptor antipsychotics that are chemically different, more effective, and free of side effects remains a challenging goal. Thus,the aim of our work is to develop novel antipsychotics that act on dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors with a low affinity for the serotonin 5-HT2C and H1 receptors, so that it could effectively cure positive symptoms, negative symptoms and cognitive impairment without the weight gain side-effect.For searching new antipsychotics candidates with exclusively intellectual property, in this thesis, arylpiperazines (piperdine) derivatives were successfully designed, synthesized and screened, then the structure-activity relationship was studied; Furthermore, the toxicity, dose-effect relationship, as well as electrocardiogram effects and pharmacokinetics of the candidates were primarily studied.(1) Four series of novel arylpiperazines (piperdine) derivatives have been designed and synthesized. The synthesis processes were fully investigated and optimized with a suitable reaction conditions have been developed. One hundred and eight new compounds were synthesized for the first time. The structures of new compounds were confirmed with NMR (Nuclear Magnetic Resonance) and MS (Mass Spectrometry).(2) The new compounds were screened with the in vitro D2, D3,5-HT1A,5-HT2A, 5-HT2C and H1 receptors binding experiments. It was found that fifteen compounds exhibited high affinities for dopamine D2 and D3, serotonin 5-HT1A and 5-HT2A receptors, with low affinity for the serotonin 5-HT2C and H1 receptors. The structure-activity relationship (SAR) was demonstrated according to the results obtained(3) An initial behavioral screening was performed on fifteen compounds on the basis of their multiple receptors affinity profile. According to the results, thirteen compounds have good dose-effect relationship. Moreover, these results indicated that the therapeutic indices of these compounds calculated between their efficacy (apomorphine or MK-801 model) and side effect (catalepsy) were greater than 10.(4) Nine compounds displaying remarkable activity were selected for the acute toxicity and electrocardiogram evaluation. The LD50 values of nine compounds exceeded 2000mg/kg, and no side-effect was observed, so they were considered extremely safe. In further electrocardiogram study, there are three compounds did not affect the electrocardiogram and without cardiac toxicity in rats(5) The optimized compound CY100611-1 exhibiting the best activity was chosen for pharmacokinetic study. Intravenous administration of CY100611-1 to rats (5 mg/kg, n=6) resulted in detectable plasma levels (half-life (t1/2)=4.99 h), The Cmax value after oral dosing was 72.14 ng/mL, AUC value was 702.74 ngxh/mL and the Tmax value was 3.0 h. The bioavailability of CY100611-1 was 32.18%.Compound CY 100611-1 showed significantly atypical antipsychotic activity, high safety factor, without cardiac toxicity and good pharmacokinetic characteristics. These optimized compounds to be useful for the novel class of drug for the treatment of schizophrenia.