α2A-肾上腺素受体的同源模建及与Yohimbine的对接研究

通过对比多个与α2A-肾上腺素受体同属G-蛋白偶联受体的视紫红质蛋白序列,选择以相似性最大的牛视紫红质蛋白为模板,同源模建了α2A-肾上腺素受体的跨膜结构,并在结构中找到了体积为0.090nm3,已被报导的活性残基包围的活性位点.运用分子力学与动力学方法研究了此结构突变前后与抑制剂Yohimbine的对接情况,得到了与文献报道相吻合的结果.同时对接研究结果发现,在α2A-肾上腺素受体的结合位点周围的一个由色氨酸和两个苯丙氨酸组成的局部疏水区对抑制剂有稳定作用,并且天冬氨酸113作为氢键受体也对稳定抑制剂有重要作用.

Yohimbine in the treatment of orgasmic dysfunction

Aim： To study the effect of yohimbine in the treatment of men with orgasmic dysfunction. Methods： A 20-mg dose of yohimbine was first given to 29 men with orgasmic dysfunction of different aetiology in the clinic. Patients were then allowed to increase the dose at home （titration） under more favourable circumstances. The outcome and side effects were subsequently assessed. Results： The patients were classified into three groups of orgasmic dysfunction： primary complete （13）, primary incomplete （8） and secondary （8）. Nocturnal emissions were present in 75%, 40% and 50% of patients in the above groups, respectively （overall average 62%）. The men presented because of fertility problems （52%） or because they wanted to experience the pleasure of orgasm （48%）. Of the 29 patients who completed the treatment, 16 managed to reach orgasm and were able to ejaculate either during masturbation or sexual intercourse. A further three achieved orgasm, but only with the additional stimulation of a vibrator. A history of preceding nocturnal emissions was present in 69% of the men in whom orgasm was induced but only 50% who failed treatment. Of the patients, two have subsequently fathered children （one set of twins） and another 3 men were also cured. Side effects were not sufficient to cause the men to cease treatment. Conclusion： Yohimbine is a useful treatment option in orgasmic dysfunction.

Dexmedetomidine Promotes Angiogenesis and Vasculogenic Mimicry in Human Hepatocellular Carcinoma through α^(2)-AR/HIF-1α/VEGFA Pathway

Objective Dexmedetomidine(DEX),the most specificα^(2)-adrenergic receptor agonist widely used for its sedative and analgesic properties,has been reported to upregulate HIF-1αexpression to protect hypoxic and ischemic tissues.However,it is largely unclear whether DEX can also upregulate Hypoxiainducible factor-1 alpha(HIF-1α)expression and its downstream vascular endothelial growth factor-A(VEGFA)in cancer tissues with oxygen-deficient tumor microenvironment.Methods We used SMMC-7721 cells,MHCC97-H cells,and a mouse model of orthotopic hepatic carcinoma to explore the effect of DEX on angiogenesis and vasculogenic mimicry(VM)and its mechanism.Under normoxic(20%O^(2))and hypoxic(1%O^(2))conditions,DEX was used to intervene cells,and yohimbine was used to rescue them.Results The results showed that DEX promoted angiogenesis and VM in human liver cancer cells within a certain dose range,and the addition of yohimbine inhibited this effect.DEX could activate HIF-1α/VEGFA pathway,which was further verified by silencing HIF-1α.Consistently,in vivo results also showed that DEX can up-regulate HIF-1α/VEGFA expression,and enhance the number of VM channels and microvessel density(MVD).Conclusion We believe that HIF-1α/VEGFA might be an important signaling pathway by which DEX promotes angiogenesis and VM formation in human hepatocellular carcinoma,whereasα^(2)-adrenergic receptor mediation might be the critical mechanisms.

Effects of α-adrenoreceptor antagonists on apoptosis and proliferation of pancreatic cancer cells in vitro

AIM: To discuss the expression of α-adrenoreceptors in pancreatic cancer cell lines PC-2 and PC-3 and the effects of α1- and α2-adrenoreceptor antagonists, yohimbine and urapidil hydrochloride, on the cell lines in vitro. METHODS: We cultured the human ductal pancreatic adenocarcinoma cell lines PC-2 and PC-3 and analyzed the mRNA expression of α1- and α2-adrenergic receptors by reverse transcription polymerase chain reaction (RT-PCR). The effects of yohimbine and urapidil hydrochloride on cell proliferation were assessed by 3-(4,5-dimethylthiasol-2-yl)- 2,4,-diphenyltetrazolium bromide (MTT) assay. Apoptosis was detected using the terminal deoxyribonucleotidyl transferase (TdT)-mediated biotin-16-dUTP nick-end labeling (TUNEL) assay and flow cytometry (FCM). RESULTS: PC-2 expressed mRNA in α1- and α2- adrenoreceptors. MTT assays showed that urapidil hydrochloride had no effect on PC-3 cell lines. However, exposure to urapidil hydrochloride increased DNA synthesis in PC-2 cell lines as compared to the control group. PC-2 cell lines were sensitive to both drugs. The proliferation of the 2 cell lines was inhibited by yohimbine. Cell proliferation was inhibited by yohimbine via apoptosis induction. CONCLUSION: The expression of α1- and α2- adrenoreceptors is different in PC-2 and PC-3 cell lines, which might be indicative of their different functions. The α2-adrenoceptor antagonist, yohimbine, can inhibit theproliferation of both cell lines and induce their apoptosis, suggesting that yohimbine can be used as an anticancer drug for apoptosis of PC-2 and PC-3 cells.

Effects of methanolic extract of <i>Pausinystalia yohimbe</i>bark on blood glucose level in normal fasting rats

Background: Pausinystalia yohimbe (L.) is a member of the family Rubiaceae. It is a valuable medicinal tree, distributed in evergreen closed-canopy forests in West Africa. It is traditionally used for treatment of erectile dysfunction and diabetes. Objective: This was an attempt to evaluate the effects of methanolic extract of P. yohimbe bark on blood glucose level in normal fasting rats. Methods: Different doses of methanolic extract of P. yohimbe bark (5, 10, 20, 40 and 80 mg/kg/mL) were orally administered to normal fasting rats to assess their effects on blood glucose levels. Results: The methanolic extract of P. yohimbe bark in different concentrations (5, 10, 20, 40 and 80 mg/kg/mL) when administered to normal fasting rats, only a considerable reduction (26.57 mg/dL) was produced by the dose of 20 mg/kg/mL. Conclusion and Recommendation: Although P. yohimbe has long been reported to regulate blood glucose levels;such effect is unclear and remains requiring further studies.

Effects of norepinephrine on dorsomedial hypothalamic nucleus of rat before and after synaptic blockade

Extracellular discharges of neurons in the dorsomedial nucleus（DMN）were recordedwith glass microelectrode from rat hypothalamic slices.The firing frequency decreased in 77 andincreased in 48 units during the addition of norepinephrine into the bath(NE,2×10-5 mol/L)of160 units when the slices were perfused with artificial cerebrospinal fluid （ACSF）.Most of theseresponses could be antagonized by Yohimbine(YOH,2×10-5～4×10-5 mol/L).Nevertheless,when the perfusion fluid was changed,i.e.,with low Ca2+-high Mg2+ ACSF（CM-ACSF）whichcould block the chemical synaptic transmission,26 out of 35 units were inhibited by NE and only1 unit excited.The inhibition could he blocked by YOH. A very significant difference（P【0.01）was seen between the data obtained in ACSF and those in CM-ACSF.Furthermore,all NE-inhibited units in ACSF were also NE-inhibited in CM-ACSF,but the majority of NE-excited u-nits in ACSF changed into NE-inhibited or NE-unresponsive in CM-ACSF.The results suggestedthat NE produced a direct inhibitory effect on neurons in DMN which was mediated by the post-synaptic alpha 2 adrenergic receptors.

The Effect of Tramadol on Blood Glucose Levels in Rats

The Background: Tramadol, is a central acting analgesic that possesses weak affinity for the μ-opioid receptor and modifies transmission of nociceptive impulses through inhibition of monoamine reuptake. This study was designed to determine the effect of tramadol on blood glucose levels and also to investigate whether or not alpha-2 adrenergic receptors were responsible for this effect. Methods: Twenty-five Wistar male rats were assigned to four groups to receive: Group I: saline;Group II: tramadol (1 mg·kg-1);Group III and Group IV: pretreatment with a2-receptor antagonist drugs yohimbine (1 mg·kg-1) or idazoxan (1 mg·kg-1), 30 min before administration of tramadol (1 mg·kg-1). Samples for plasma glucose measurement were withdrawn at 0, 30, 60, 90 and 120 minutes of the experiment. Results: A significant rise in blood glucose levels was observed following administration of i.v. tramadol. Pretreatment with both yohimbine and idazoxan (1 mg·kg-1) significantly attenuated tramadol-induced hyperglycemia. Conclusion: The results of the study indicate that, tramadol administered at an analgesic dose of 1 mg·kg-1 produces hyperglycemia in diethyl ether anesthetized rats. Reversal of this effect with a2-adrenoceptor blocking agents suggests that monoaminergic pathways which contribute to the analgesic action of tramadol, may have a role in the hyperglycemic action of the drug.

Synthetic studies towards(-)-deserpidine:Total synthesis of the stereoisomer and derivative of (-)-deserpidine

The asymmetric synthesis of 16,17,20-epi-deserpidine and a derivative of(-)-deserpidine has been achieved.Key feature s in the assembly of the pentacyclic framework include a visible-light photocatalytic intra-/inter-/intramolecular radical cascade reaction to construct the tetracyclic ABCD ring system in one-pot and an intramolecularaldol reaction to forge the cyclohexane E ring.