Carbazole and tetrahydro-carboline derivatives as dopamine D3 receptor antagonists with the multiple antipsychotic-like properties

Dopamine D3 receptor (D3R) is implicated in multiple psychotic symptoms. Increasing the D3R selectivity over dopamine D2 receptor (D2R) would facilitate the antipsychotic treatments. Herein, novel carbazole and tetrahydro-carboline derivatives were reported as D3R selective ligands. Through a structure-based virtual screen, ZLG-25 (D3R Ki = 685 nmol/L; D2R Ki > 10,000 nmol/L) was identified as a novel D3R selective bitopic ligand with a carbazole scaffold. Scaffolds hopping led to the discovery of novel D3R-selective analogs with tetrahydro-β-carboline or tetrahydro-γ-carboline core. Further functional studies showed that most derivatives acted as hD3R-selective antagonists. Several lead compounds could dose-dependently inhibit the MK-801-induced hyperactivity. Additional investigation revealed that 23j and 36b could decrease the apomorphine-induced climbing without cataleptic reaction. Furthermore, 36b demonstrated unusual antidepressant-like activity in the forced swimming tests and the tail suspension tests, and alleviated the MK-801-induced disruption of novel object recognition in mice. Additionally, preliminary studies confirmed the favorable PK/PD profiles, no weight gain and limited serum prolactin levels in mice. These results revealed that 36b provided potential opportunities to new antipsychotic drugs with the multiple antipsychotic-like properties.

Expression and clinical significance of PHH3 and β-catenin in the tissue of non-small cell lung cancer / 中国基层医药

Objective To investigate the expression and clinical significance of PHH 3 and β-catenin in non-small cell lung cancer ( NSCLC) .Methods 78 cases of NSCLC tissue removed from June 2013 to June 2017 in Rizhao Central Hospital were collected .The expression of PHH3 and β-catenin protein in NSCLC and 30 cases of normal lung tissues were detected by immunohistochemical MaxVision method .The relationship between the expres-sion of PHH3 andβ-catenin protein was analyzed .The relationship between the expression of PHH 3,β-catenin and the clinicopathological features of NSCLC was analyzed .Results The positive rate of PHH3 in NSCLC tissues ( 57/78,73.1％) was significantly higher than that in normal lung tissues (2/30,6.7％)(χ2 =38.553,P<0.05).The expression level of PHH3 was significantly correlated with tumor differentiation (χ2 =5.248,P<0.05),lymph node metastasis(χ2 =7.747,P<0.05),but it was not related to the age (χ2 =0.209,P>0.05),gender(χ2 =0.033,P>0.05) and pathological type (χ2 =0.190,P>0.05).The positive rate of β-catenin in NSCLC tissues (54/78, 69.2％) was significantly higher than that in normal lung tissues (3/30,10.0％) (χ2 =30.499,P <0.05).The expression level of β-catenin was significantly correlated with tumor differentiation (χ2 =4.934,P<0.05),lymph node metastasis(χ2 =8.098,P<0.05),but it was not related to the age (χ2 =0.006,P>0.05),gender(χ2 =0.595,P>0.05) and pathological type (χ2 =0.071,P>0.05).The expression of PHH3 was positively correlated withβ-catenin(r=0.597,P<0.05).Kaplan-Meier analysis showed that PHH3 and β-catenin expression was negatively correlated with prognosis .Conclusion The overexpression of PHH3 and β-catenin in NSCLC may be related to the development ,invasion and metastasis of NSCLC ,which is expected to be an indicator of NSCLC ,and to predict invasion and metastasis .