Synthesis, binding, and functional properties of tetrahydroisoquinolino-2-alkyl phenones as selective σ2R/TMEM97 ligands.

Sigma-2 receptor (σ2R/TMEM97) has been implicated to play important roles in multiple cellular dysfunctions, such as cell neoplastic proliferation, neuro-inflammation, neurodegeneration, etc. Selective σ2 ligands are believed to be promising pharmacological tools to regulate or diagnose various disorders. As an ongoing effort of discovery of new and selective σ2 ligands, we have synthesized a series of tetrahydroisoquinolino-2-alkyl phenone analogs and identified that 10 of them have moderate to potent affinity and selectivity for σ2R/TMEM97. Especially, 4 analogs showed Ki values ranging from 0.38 to 5.1 nM for σ2R/TMEM97 with no or low affinity for sigma-1 receptor (σ1R). Functional assays indicated that these 4 most potent analogs had no effects on intracellular calcium concentration and were classified as putative σ2R/TMEM97 antagonists according to current understanding. The σ2R/TMEM97 has been suggested to play important roles in the central nervous system. Based on published pharmacological and clinical results from several regarded σ2R/TMEM97 antagonists, these analogs may potentially be useful for the treatment of various neurodegenerative diseases.

Synthesis and evaluation of tetrahydroindazole derivatives as sigma-2 receptor ligands.

A series of tetrahydroindazole derivatives were synthesized and evaluated for their affinities for both sigma-1 and sigma-2 receptors. These compounds are hybrid structures of a tetrahydroindazole substituted benzamide and a 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety or a 9-azabicyclo[3.3.1]nonan-3-yl-amine moiety. These newly synthesized hybrid analogs showed various affinities for sigma-2 receptor without any significant affinities for sigma-1 receptor. In particular, compounds 12, 15b, 15c, and 15d, demonstrated moderate affinity and excellent selectivity for sigma-2 receptor. It is interesting to note that 3-5 carbon units between the tetrahydroindazole substituted benzamide and the 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline moiety are appropriate for sigma-2 receptor binding. No substitution on the 9-aza nitrogen is proper for sigma-2 affinity in the 2-(9-azabicyclo[3.3.1]nonan-3-yl-amino)-4-(3,6,6-trimethyl-4-oxo-4,5,6,7-tetrahydro-1H-indazol-1-yl)benzamide analogs.

[Observation on therapeutic effect of electroacupuncture for treatment of sudden hearing loss].

OBJECTIVE: To observe the therapeutic effect of electroacupuncture for treatment of sudden hearing loss and to compare with western medicine therapy. METHODS: Sixty cases were randomly divided into an electroacupuncture group and a medication group, 30 cases in each group. The electroacupuncture group was treated with electroacupuncture at Tinghui (GB 2), Yifeng (TE 17), Hegu (LI 4), Xiaxi (GB 43), Zhongzhu (TE 3), etc. and the medication group with intravenous dripping of 6% low molecule dextran 500 mL with ATP and coenzyme A, and oral administration of Nimodipine, Gold Theragan. Whole blood specific viscosity, plasma specific viscosity, hematocrit and fibrinogen before and after treatment and their therapeutic effects were observed. RESULTS: The total effective rate was 86.7 in the electroacupuncture group and 60.0% in the medication group with a significant difference between the two groups (P<0.05), the former being better than the latter; there were significant differences in whole blood specific viscosity, plasma specific viscosity, hematocrit and fibrinogen before and after treatment in the electroacupuncture group (P<0.05), and with no significant difference in the medication group (P>0.05) before and after treatment, and with a significant difference in whole blood specific viscosity, plasma specific viscosity and fibrinogen between the two groups (P<0.05). CONCLUSION: Electroacupuncture has a significant therapeutic effect on sudden hearing loss, which is better than that of the medication, and the mechanism is possibly related with regulative action on indexes of blood rheology.

[Effects of Feiji Formula on lung cancer metastasis in mice].

OBJECTIVE: To observe the effects of Feiji Formula, a compound traditional Chinese herbal medicine, on lung cancer metastasis in mice. METHODS: The lung cancer metastasis model of mice was established in this experiment study. Twenty-four mice were randomly divided into three groups: untreated group, cisplatin group and Feiji Formula group. Mice in the Feiji Formula group were treated with Feiji Formula decoction; in cisplatin group, with cisplatin by intraperitoneal injection; and in the untreated group, with normal saline (NS). After twenty-day treatment, the body and tumor weights as well as the number of metastatic tumors in both lungs of each mouse were measured. RESULTS: The body weight of mice in cisplatin group was significantly less than that of Feiji Formula group and untreated group (P<0.01); the tumor weight of mice in cisplatin group and Feiji Formula group was markedly lower than that of untreated group (P<0.01); and the number of metastatic tumors in cisplatin group and Feiji Formula group was markedly lower than that of the untreated group (P<0.01), no significant difference between the Feiji Formula group and cisplatin group in terms of the weights and the numbers of metastatic tumors in bilateral lungs. CONCLUSION: Feiji Formula can suppress tumor growth and decrease the number of lung metastatic tumors in the mice, and maintain the body weight of the mice.

[Intervention effect of Feiji Recipe on immune escape of lung cancer].

OBJECTIVE: To evaluate the intervention effect of Feiji Recipe (FJR) on tumor immune escape. METHODS: In the prospective randomized control study, 60 cases of middle stage and advanced non-small cell lung cancer (NSCLC) with qi-yin deficiency syndrome were randomly assigned to the treatment group and the control group, 30 in each group. The levels of CD+ CD25+ Tr, interleukin-10 (IL-10), vascular endothelial growth factor (VEGF), sCD44v6 and transforming growth factor-beta1 (TGF-beta1) of peripheral blood were observed before and after treatment, and the clinical efficacy of FJR was evaluated depending upon the changes in tumor size, Karnofsky Performance scoring (KPS) and TCM syndrome. RESULTS: (1) The levels of CD4+ CD2+Tr, VEGF, sCD44v6, TGF-beta1, and IL-10 decreased, in the treatment group as compared with those in the control group, respectively. (2) The stabilization rate of tumor in the treatment group was superior to that in the control group (78.26% vs 50.00%, P < 0.05). (3) The stabilization rate of KPS increasing in the treatment group and the control group was 76.67% and 43.33% respectively, suggesting the improvement of KPS in the treatment group was superior to that in the control group (P < 0.01). (4) Improvement in TCM qi-yin deficiency syndrome was more significant in the treatment group than that in the control group. CONCLUSION: FJR can stabilize the tumor body, improve the clinical symptoms of middle stage and advanced NSCLC with qi-yin deficiency syndrome, promote patients' quality of life, and is effective in recovering immuno-surveillance and intervening immune escape of lung cancer through multi-pathway to enhance the clinical therapeutic efficacy.