Abstract
TPN672 [7-(2-(4-(benzothiophen-4-yl) piperazin-1-yl)ethyl)quinolin-2(1H)-one maleate] is a novel antipsychotic candidate with high affinity for serotonin and dopamine receptors that is currently in clinical trial for the treatment of psychiatric disorders. In vitro binding study showed that TPN672 exhibited extremely high affinity for serotonin 1A receptor (5-HT1AR) (K i = 0.23 nM) and 5-HT2AR (K i = 2.58 nM) as well as moderate affinity for D3R (K i = 11.55 nM) and D2R (K i = 17.91 nM). In vitro functional assays demonstrated that TPN672 acted as a potent 5-HT1AR agonist, D2R/D3R partial agonist, and 5-HT2AR antagonist. TPN672 displayed robust antipsychotic efficacy in rodent models (e.g., blocking phencyclidine-induced hyperactivity), significantly better than aripiprazole, and ameliorated negative symptoms and cognitive deficits in the sociability test, dark avoidance response, Morris water maze test, and novel object recognition test. The results of electrophysiological experiments showed that TPN672 might inhibit the excitability of the glutamate system through activating 5-HT1AR in medial prefrontal cortex, thereby improving cognitive and negative symptoms. Moreover, the safety margin (the ratio of minimum catalepsy-inducing dose to minimum effective dose) of TPN672 was about 10-fold, which was superior to aripiprazole. In conclusion, TPN672 is a promising new drug candidate for the treatment of schizophrenia and has been shown to be more effective in attenuating negative symptoms and cognitive deficits while having lower risk of extrapyramidal symptoms and hyperprolactinemia. SIGNIFICANCE STATEMENT: TPN672 is a promising new drug candidate for the treatment of schizophrenia and has been shown to be more effective in attenuating negative symptoms and cognitive deficits while having a lower risk of extrapyramidal symptoms and hyperprolactinemia. A phase I clinical trial is now under way to test its tolerance, pharmacokinetics, and pharmacodynamic effects in human volunteers. Accordingly, the present results will have significant impact on the development of new antischizophrenia drugs.
Highlights
Schizophrenia is a severe psychiatric disorder that has profoundly affects both the individuals affected and society
The results showed that TPN672 (10 μM) induced a significant decrease in the amplitude of eEPSCs to 67.51 ± 3.97% of the control (n = 10, P < 0.001, paired t test) and this inhibitory effect of TPN672 on glutamatergic eEPSCs could be washed out.To confirm whether the decreased glutamatergic transmission via a presynaptic mechanism, we further examined the effect of TPN672 on the paired pulse ratio (PPR)
We found that TPN672 (0.3 mg/kg, p.o.) and aripiprazole (3 mg/kg, p.o.) shown no significant difference in serum prolactin level compared with the vehicle-treated mice (Fig 7), while risperidone (0.1 mg/kg) induced a significant increase (p=0.0099 vs. vehicle) (Fig 7)
Summary
Schizophrenia is a severe psychiatric disorder that has profoundly affects both the individuals affected and society. Schizophrenia is characterized by diverse psychopathology; the core features are positive symptoms (delusions and hallucinations; so-called psychotic symptoms in which contact with reality is lost), negative symptoms (impaired motivation, reduction in spontaneous speech, and social withdrawal), and cognitive impairment (temporary or permanent loss of mental function) Kahn et al 2015; Owen et al 2016; Krogmann et al 2019).Schizophrenia is characterized by a sequential trajectory that involves four phases: premorbid phase, prodromal phase, psychotic phase and stable phase(Kelly et al 2019). The psychotic phase is the formal onset of schizophrenia and is marked by repeated episodes of florid positive symptoms. The negative and cognitive symptoms are associated with long-term effects on social function
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