Sigma-2 Receptor as a Potential Drug Target.

Sigma-2 receptor plays key roles in promoting tumor cell apoptosis, enhancing efficacy of anti-tumor drugs, blocking signal transduction controlled by Aß oligomers, regulating Ca2+ homeostasis and protecting nerve cells. Studies indicated that sigma-2 receptor may be closely coupled with ROS, LDL, mTOR, RAS, PLC/PKC, lysosomal autophagy and mitochondrial super oxidative stress. In addition, the high expression of this receptor in proliferating cells and nerve cells indicates that sigma-2 receptor is an ideal molecular target for imaging and therapeutic development for cancer, Alzheimer's disease, schizophrenia and traumatic brain injury. Various sigma-2 agonists have shown promising anticancer activities, while sigma-2 antagonists have displayed neuroprotection and inhibition of Aß oligomers in the brain of Alzheimer's disease patients. Thus, both sigma-2 agonists and antagonists are potentially useful therapeutics for the management of cancer and neurodegenerative disorders.

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.

Sigma ligands as potent inhibitors of Aß and AßOs in neurons and promising therapeutic agents of Alzheimer's disease.

Alzheimer's disease (AD) is an age-related neurodegenerative disease and characterized by dementia, memory decline, loss of learning and cognitive disorder. The main pathological features of AD are the deposition of amyloid plaques and the formation of neurofibrillary tangles (NFTs) in the brain. The current anti-AD drugs have shown unsatisfactory therapeutic results. Due to the complications and unclear pathogenesis, AD is still irreversible and incurable. Among several hypotheses proposed by the academic community, the amyloid cascade is widely recognized by scholars and supported by a large amount of evidences. However, controversy over pathogenic factors has also been ongoing. Increasing evidence has shown that amyloid-ß (Aß) and especially amyloid-ß oligomers (AßOs) are highly neurotoxic and pathogenic agents that damage neurons, mediate various receptors in the downstream pathways, and ultimately lead to learning and cognitive dysfunction. However, efforts in developing inhibitors of Aß or amyloid-ß precursor protein (APP) have all failed to yield good clinical results. More recently, it has been demonstrated that sigma receptors, including sigma-1 and sigma-2 subtypes, may play critical roles in the regulation of binding and metabolism of AßOs in neuron cells and the pathophysiology of AD. Thus, sigma receptor ligands are being recognized as promising therapeutic agents for treating or ameliorating AD. This article will review the pathophysiology of AD and highlight the sigma ligands that display the capability of preventing or even reversing Aß- and AßOs-induced neurotoxicity and blocking the signal transduction caused by AßOs.

Synthesis and evaluation of pyrimidoindole analogs in umbilical cord blood ex vivo expansion.

The scarcity of hematopoietic stem cells (HSCs) significantly hindered their clinical potentials. Umbilical cord blood (UCB) has become the leading source of HSCs for both research and clinical applications. But the low content of HSCs in a single UCB unit limited its use only to pediatric patients. Various cytokines and small molecules have demonstrated strong abilities in promoting HSC ex vivo expansion, of which UM171 is the newest and by far the most potent HSC ex vivo expansion agent. In this study, we synthesized 37 pyrimidoindole analogs and identified 6 compounds to be potent in promoting HSC ex vivo expansion. In particular, analog 11 was found to be the most effective in stimulating ex vivo expansion of UCB CD34+ cells and CD34+CD38- cells. Initial data indicated that compound 11 promoted the absolute number of long term HSCs and inhibited their differentiation. UCB HSCs expanded with 11 retained adequate multi-lineage differentiation capacity. In addition, compound 11 is not cytotoxic at its test concentrations, suggesting that it merits further investigation for potential clinical applications.

Isolation, synthesis, and cytotoxicity evaluation of two impurities in nomegestrol acetate.

Nomegestrol acetate (NOMAc) is a synthetic progesterone analog and classified as a fourth-generation progestin. It has been approved in many countries for oral contraception, hormonal replacement therapy (HRT), and treatment of various gynecological disorders. There are several synthetic routes reported for the synthesis of NOMAc and they all share the very similar last three to five steps toward the conversion of 6-methylene to 6-methyl-6,7-unsaturated structure. Therefore the final product from different processing routes may have similar impurity profiles. In the analysis of NOMAc, we identified two impurities, impurity A (listed in EP 8.0) and impurity B (not specified in EP 8.0). Both impurities were further confirmed by synthesis. In addition, both impurities and NOMAc were evaluated for their in vitro cytotoxicities against L02 liver cells, mesenchymal stem cells, MCF-7 breast cancer cells, and C33A cervical cancer cells. These three analogs are not cytotoxic to the four cell lines at low concentrations (<20 µM). NOMAc and impurity A showed cytotoxicity to L02, MCF-7, and C33A cells at high concentrations, while impurity B did not show significant cytotoxicity to any of the cell lines tested.

Synthesis and pharmacological evaluation of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives as sigma-2 receptor ligands.

Increasing evidences have implicated that sigma-2 receptor is a biomarker and significantly over-expressed in many proliferative cancer cells with no or low expression in normal cells. Sigma-2 receptor selective ligands have been successfully used as valuable tools to study its pharmacological functions, tumor imaging, and cancer therapeutics or adjuvants. 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinolinylalkyl benzamides are among a few categories of structures that have demonstrated high affinities and selectivities for sigma-2 receptor and been used extensively as study tools in various tumor imaging and therapy. As a continuous effort, we have synthesized a new series of 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives and evaluated their affinities for both sigma-1 and sigma-2 receptors. Most of these newly developed analogs showed good to excellent binding affinities for sigma-2 receptor with no or low affinities for sigma-1 receptor. In particular, compounds 3b, 3e, 4b, and 4e demonstrated Ki values of 5-6 nM affinities and excellent selectivities for sigma-2 receptor. In addition, these analogs also demonstrated moderate anticancer activities against human liver Huh-7 tumor cells and human esophagus KYSE-140 cancer cells. But their cytotoxicities seem not to be correlated with their sigma-2 receptor affinities.

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.

Sigma-2 receptor ligands and their perspectives in cancer diagnosis and therapy.

The sigma-2 receptor is highly expressed in various rapidly proliferating cancer cells and regarded as a cancer cell biomarker. Selective sigma-2 ligands have been shown to specifically label the tumor sites, induce cancer cells to undergo apoptosis, and inhibit tumor growth. Sigma-2 ligands are potentially useful as cancer diagnostics, anticancer therapeutics, or adjuvant anticancer treatment agents. However, both the cloning of this receptor and the identification of its endogenous ligand have not been successful, and the lack of structural information has severely hindered the understanding of its physiological roles, its signaling pathways, and the development of more selective sigma-2 ligands. Recent data have implicated that sigma-2 binding sites are within the lipid rafts and that PGRMC1 (progesterone receptor membrane component 1) complex and sigma-2 receptor may be coupled with EGFR (epidermal growth factor receptor), mTOR (mammalian target of rapamycin), caspases, and ion channels. Due to its promising applications in cancer management, there are rapidly increasing research efforts that are being directed into this field. This review article updates the current understanding of sigma-2 receptor and its potential physiological roles, applications, interaction with other effectors, with special focuses on the development of sigma-2 ligands, their chemical structures, pharmacological profiles, applications in imaging and anticancer therapy.

catena-Poly[[[aqua-(1,10-phenanthro-line)manganese(II)]-µ-adamantane-1,3-dicarboxyl-ato] monohydrate].

In the title coordination polymer, {[Mn(C(12)H(14)O(4))(C(12)H(8)N(2))(H(2)O)]·H(2)O}(n), the Mn(II) atom has a highly distorted cis-MnN(2)O(4) octa-hedral geometry arising from its coordination by a bidentate phenanthroline ligand, a water mol-ecule and monodentate and bidentate adamantane-1,3-dicarboxyl-ate dianions. The bridging dianion leads to [001] chains in the crystal. The chains are linked by O-H⋯O hydrogen bonds, involving both the coordinated and uncoordinated water mol-ecules, thereby forming a two-dimensional network.

[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.

[Changes of trace elements in regional lymph nodes of gastric carcinoma].

OBJECTIVE: To explore the relationship between the changes of trace elements and lymphatic metastasis in gastric carcinoma. METHODS: Trace elements including Fe, Mg, Mn, Ca, Cu, Zn, Se were measured in primary gastric carcinoma and regional lymph nodes from 40 patients with gastric carcinoma, and compared among the primary tumor, metastatic, and non-metastatic nodes. RESULTS: There were no significant differences in the contents of Fe, Mg, Mn and Ca among primary gastric tumors, regional lymph nodes with or without metastasis (P=0.372 - 0.741, P > 005), and no significant differences in the contents of all 7 trace elements between primary tumors and metastatic lymph nodes (P=0.15 - 0.59, P > 005). Compared with metastatic lymph nodes, the contents of Zn, Se significantly decreased, while Cu and Cu/Zn significantly increased (P=0.001 - 0.009, P< 0.01) in non-metastatic lymph nodes. The content of Zn in N2 positive lymph nodes was significant lower than that in N1 positive nodes (P=0.027). There were no significant difference in the contents of all 7 elements between intestinal type and diffuse type (P=0.149 - 0.758, P > 0.05). CONCLUSIONS: Lymphatic metastasis of gastric cancer is concomitant with the changes of trace elements, and the changes of Zn, Cu, Se may be related with lymphatic metastasis.

[Effect of saikosaponins on epileptic rat electroenciphalogram].

OBJECTIVE: To study the effect of saikosaponins on the electroencephalogram (EEG) of epileptic rats to evaluate its therapeutic effect against epilepsies. METHODS: Sixty 8-week-old healthy SD rats were randomized into normal control group (A), epileptic model group (B), lamotrigine group (C), and 3 saikosaponin groups of small, moderate and high doses (D, E, and F groups, respectively), with 10 rats in each group. Penicillin was used to induce epilepsy in the latter 5 groups, and the EEG and onset of epileptic seizures were observed in each group. RESULTS: In group B, the EEG contained obvious epileptic discharges, which were not found in that in group A. After treatment with saikosaponins and lamotrignie, the EEG of group C and F became normal, whereas the EEG in group D still contained epileptic discharges at a low level, and that in group E was basically normal. The EEGs of group C, D, E, and F were significantly different from that in group B (P<0.001). CONCLUSION: Saikosaponins can obviously alleviate the severity of epileptic seizure in epileptic rats.