Discovery of the covalent SARS-CoV-2 Mpro inhibitors from antiviral herbs via integrating target-based high-throughput screening and chemoproteomic approaches.

The main proteases (Mpro ) are highly conserved cysteine-rich proteins that can be covalently modified by numerous natural and synthetic compounds. Herein, we constructed an integrative approach to efficiently discover covalent inhibitors of Mpro from complex herbal matrices. This work begins with biological screening of 60 clinically used antiviral herbal medicines, among which Lonicera japonica Flos (LJF) demonstrated the strongest anti-Mpro effect (IC50 = 37.82 µg/mL). Mass spectrometry (MS)-based chemical analysis and chemoproteomic profiling revealed that LJF extract contains at least 50 constituents, of which 22 exhibited the capability to covalently modify Mpro . We subsequently verified the anti-Mpro effects of these covalent binders. Gallic acid and quercetin were found to potently inhibit severe acute respiratory syndrome coronavirus 2 Mpro in dose- and time- dependent manners, with the IC50 values below 10 µM. The inactivation kinetics, binding affinity and binding mode of gallic acid and quercetin were further characterized by fluorescence resonance energy transfer, surface plasmon resonance, and covalent docking simulations. Overall, this study established a practical approach for efficiently discovering the covalent inhibitors of Mpro from herbal medicines by integrating target-based high-throughput screening and MS-based assays, which would greatly facilitate the discovery of key antiviral constituents from medicinal plants.

Cytokine Storm in Acute Viral Respiratory Injury: Role of Qing-Fei-Pai-Du Decoction in Inhibiting the Infiltration of Neutrophils and Macrophages through TAK1/IKK/NF-[Formula: see text]B Pathway.

COVID-19 has posed unprecedented challenges to global public health since its outbreak. The Qing-Fei-Pai-Du decoction (QFPDD), a Chinese herbal formula, is widely used in China to treat COVID-19. It exerts an impressive therapeutic effect by inhibiting the progression from mild to critical disease in the clinic. However, the underlying mechanisms remain obscure. Both SARS-CoV-2 and influenza viruses elicit similar pathological processes. Their severe manifestations, such as acute respiratory distress syndrome (ARDS), multiple organ failure (MOF), and viral sepsis, are correlated with the cytokine storm. During flu infection, QFPDD reduced the lung indexes and downregulated the expressions of MCP-1, TNF-[Formula: see text], IL-6, and IL-1[Formula: see text] in broncho-alveolar lavage fluid (BALF), lungs, or serum samples. The infiltration of neutrophils and inflammatory monocytes in lungs was decreased dramatically, and lung injury was ameliorated in QFPDD-treated flu mice. In addition, QFPDD also inhibited the polarization of M1 macrophages and downregulated the expressions of IL-6, TNF-[Formula: see text], MIP-2, MCP-1, and IP-10, while also upregulating the IL-10 expression. The phosphorylated TAK1, IKK[Formula: see text]/[Formula: see text], and I[Formula: see text]B[Formula: see text] and the subsequent translocation of phosphorylated p65 into the nuclei were decreased by QFPDD. These findings indicated that QFPDD reduces the intensity of the cytokine storm by inhibiting the NF-[Formula: see text]B signaling pathway during severe viral infections, thereby providing theoretical and experimental support for its clinical application in respiratory viral infections.

Inhibition of drug-metabolizing enzymes by Jingyin granules: implications of herb-drug interactions in antiviral therapy.

Jingyin granules, a marketed antiviral herbal medicine, have been recommended for treating H1N1 influenza A virus infection and Coronavirus disease 2019 (COVID-19) in China. To fight viral diseases in a more efficient way, Jingyin granules are frequently co-administered in clinical settings with a variety of therapeutic agents, including antiviral drugs, anti-inflammatory drugs, and other Western medicines. However, it is unclear whether Jingyin granules modulate the pharmacokinetics of Western drugs or trigger clinically significant herb-drug interactions. This study aims to assess the inhibitory potency of the herbal extract of Jingyin granules (HEJG) against human drug-metabolizing enzymes and to clarify whether HEJG can modulate the pharmacokinetic profiles of Western drug(s) in vivo. The results clearly demonstrated that HEJG dose-dependently inhibited human CES1A, CES2A, CYPs1A, 2A6, 2C8, 2C9, 2D6, and 2E1; this herbal medicine also time- and NADPH-dependently inhibited human CYP2C19 and CYP3A. In vivo tests showed that HEJG significantly increased the plasma exposure of lopinavir (a CYP3A-substrate drug) by 2.43-fold and strongly prolonged its half-life by 1.91-fold when HEJG (3 g/kg) was co-administered with lopinavir to rats. Further investigation revealed licochalcone A, licochalcone B, licochalcone C and echinatin in Radix Glycyrrhizae, as well as quercetin and kaempferol in Folium Llicis Purpureae, to be time-dependent CYP3A inhibitors. Collectively, our findings reveal that HEJG modulates the pharmacokinetics of CYP substrate-drug(s) by inactivating CYP3A, providing key information for both clinicians and patients to use herb-drug combinations for antiviral therapy in a scientific and reasonable way.

Enhanced anti-tumor efficacy by inhibiting HIF-1α to reprogram TAMs via core-satellite upconverting nanoparticles with curcumin mediated photodynamic therapy.

Tumor hypoxic stress after photodynamic therapy (PDT) will be inevitably exacerbated by the vascular blocking effects and oxygen consumption in the tumor microenvironment (TME) which usually leads to compromised efficacy and clinical performance. Increasing evidence links the hypoxia induced up-regulation of hypoxia inducible factor 1α (HIF-1α) with immunosuppressive TME, including the polarization of M2 phenotype tumor associated macrophages (TAMs), which promote the recurrence and metastasis. Here, we reported NIR-triggered core-satellite upconverting nanoparticles (CSNPs) with curcumin (Cur) embedded as a difunctional photosensitizer, which could realize PDT in deep tumors with long excitation wavelength (980 nm) and reverse the immunosuppressive TME induced by up-regulated HIF-1α at the same time. This Cur-loaded CSNPs (Cur-CSNPs)-mediated PDT could successfully induce the immunogenic cell death (ICD) of triple negative breast cancer (TNBC) cell lines (4T1 and MDA-MB-231) in vitro and repolarize the 4T1 cells co-cultured TAMs from pro-tumor M2 to the anti-tumor M1 phenotype. Furthermore, Cur-CSNPs-mediated PDT could suppress the 4T1 tumor growth in primary and distant sites through the synergistic immunotherapeutic effects in vivo by priming M1 type TAMs and CD4+/CD8+ T cells' infiltration. Our data highlight the novel application of CSNPs-embedded Cur as a difunctional photosensitizer to enhance the anti-tumor efficacy of PDT.

Discovery of naturally occurring inhibitors against SARS-CoV-2 3CLpro from Ginkgo biloba leaves via large-scale screening.

3-Chymotrypsin-like protease (3CLpro) is a virally encoded main proteinase that is pivotal for the viral replication across a broad spectrum of coronaviruses. This study aims to discover the naturally occurring SARS-CoV-2 3CLpro inhibitors from herbal constituents, as well as to investigate the inhibitory mechanism of the newly identified efficacious SARS-CoV-2 3CLpro inhibitors. Following screening of the inhibitory potentials of eighty herbal products against SARS-CoV-2 3CLpro, Ginkgo biloba leaves extract (GBLE) was found with the most potent SARS-CoV-2 3CLpro inhibition activity (IC50 = 6.68 µg/mL). Inhibition assays demonstrated that the ginkgolic acids (GAs) and the bioflavones isolated from GBLE displayed relatively strong SARS-CoV-2 3CLpro inhibition activities (IC50 < 10 µM). Among all tested constituents, GA C15:0, GA C17:1 and sciadopitysin displayed potent 3CLpro inhibition activities, with IC50 values of less than 2 µM. Further inhibition kinetic studies and docking simulations clearly demonstrated that two GAs and sciadopitysin strongly inhibit SARS-CoV-2 3CLprovia a reversible and mixed inhibition manner. Collectively, this study found that both GBLE and the major constituents in this herbal product exhibit strong SARS-CoV-2 3CLpro inhibition activities, which offer several promising leading compounds for developing novel anti-COVID-19 medications via targeting on 3CLpro.

Inhibition of drug-metabolizing enzymes by Qingfei Paidu decoction: Implication of herb-drug interactions in COVID-19 pharmacotherapy.

Corona Virus Disease 2019 (COVID-19) has spread all over the world and brings significantly negative effects on human health. To fight against COVID-19 in a more efficient way, drug-drug or drug-herb combinations are frequently used in clinical settings. The concomitant use of multiple medications may trigger clinically relevant drug/herb-drug interactions. This study aims to assay the inhibitory potentials of Qingfei Paidu decoction (QPD, a Chinese medicine compound formula recommended for combating COVID-19 in China) against human drug-metabolizing enzymes and to assess the pharmacokinetic interactions in vivo. The results demonstrated that QPD dose-dependently inhibited CYPs1A, 2A6, 2C8, 2C9, 2C19, 2D6 and 2E1 but inhibited CYP3A in a time- and NADPH-dependent manner. In vivo test showed that QPD prolonged the half-life of lopinavir (a CYP3A substrate-drug) by 1.40-fold and increased the AUC of lopinavir by 2.04-fold, when QPD (6 g/kg) was co-administrated with lopinavir (160 mg/kg) to rats. Further investigation revealed that Fructus Aurantii Immaturus (Zhishi) in QPD caused significant loss of CYP3A activity in NADPH-generating system. Collectively, our findings revealed that QPD potently inactivated CYP3A and significantly modulated the pharmacokinetics of CYP3A substrate-drugs, which would be very helpful for the patients and clinicians to avoid potential drug-interaction risks in COVID-19 treatment.

Targeting CTGF in Cancer: An Emerging Therapeutic Opportunity.

Despite the dramatic advances in cancer research over the decades, effective therapeutic strategies are still urgently needed. Increasing evidence indicates that connective tissue growth factor (CTGF), a multifunctional signaling modulator, promotes cancer initiation, progression, and metastasis by regulating cell proliferation, migration, invasion, drug resistance, and epithelial-mesenchymal transition (EMT). CTGF is also involved in the tumor microenvironment in most of the nodes, including angiogenesis, inflammation, and cancer-associated fibroblast (CAF) activation. In this review, we comprehensively discuss the expression of CTGF and its regulation, oncogenic role, clinical relevance, targeting strategies, and therapeutic agents. Herein, we propose that CTGF is a promising cancer therapeutic target that could potentially improve the clinical outcomes of cancer patients.

Compound-based Chinese medicine formula: From discovery to compatibility mechanism.

ETHNOPHARMACOLOGICAL RELEVANCE: Chinese medicine formula (CMF) has a long history of clinical use in the treatment of various diseases under the guidance of traditional Chinese medicine (TCM) theory. The application of CMF can be divided into three levels, crude extracts, homologous compounds mixture, and specific compounds. However, the modern scientific connotation of the CMF theory has not been clarified. AIM OF THE REVIEW: To critically evaluate the research strategy for the investigation of compound-based CMF (CCMF). MATERIALS AND METHODS: The related information was collected from the scientific databases, including CNKI, Elsevier, ScienceDirect, PubMed, SpringerLink, Web of Science, and Wiley Online. RESULTS: The research design including discovery, screening, optimization, pharmacodynamics models, and target research techniques including the targets for compatibility compounds were evaluated. Essentially it has been evaluated that the in vitro multicellular three-dimensional culture or organoid model has been proposed for the optimization model for compatibility research of CCMF. Based on these, the traditional compatibility theory of CMF, such as Monarch-Minister-Assistant-Guide (Jun-Chen-Zuo-Shi in Chinese), can probably be elucidated by the CCMF research. CONCLUSIONS: CCMF has the clear advantage of providing the exact composition and controllable quality of modern medicines, in addition to having the characteristics of multi-ingredients and multi-targets synergistic effects of TCM. However, CCMF is still associated with challenges which need to be addressed for its future use.

Raddeanin A, a triterpenoid saponin isolated from Anemone raddeana, suppresses the angiogenesis and growth of human colorectal tumor by inhibiting VEGFR2 signaling.

Raddeanin A (RA) is an active triterpenoid saponin from a traditional Chinese medicinal herb, Anemone raddeana Regel. It was previously reported that RA possessed attractive antitumor activity through inhibiting proliferation and inducing apoptosis of multiple cancer cells. However, whether RA can inhibit angiogenesis, an essential step in cancer development, remains unknown. In this study, we found that RA could significantly inhibit human umbilical vein endothelial cell (HUVEC) proliferation, motility, migration, and tube formation. RA also dramatically reduced angiogenesis in chick embryo chorioallantoic membrane (CAM), restrained the trunk angiogenesis in zebrafish, and suppressed angiogenesis and growth of human HCT-15 colorectal cancer xenograft in mice. Western blot assay showed that RA suppressed VEGF-induced phosphorylation of VEGFR2 and its downstream protein kinases including PLCγ1, JAK2, FAK, Src, and Akt. Molecular docking simulation indicated that RA formed hydrogen bonds and hydrophobic interactions within the ATP binding pocket of VEGFR2 kinase domain. Our study firstly provides the evidence that RA has high antiangiogenic potency and explores its molecular basis, demonstrating that RA is a potential agent or lead candidate for antiangiogenic cancer therapy.

Antiangiogenic triterpenes isolated from Chinese herbal medicine Actinidia chinensis Planch.

Actinidia chinensis Planch. is a famous Chinese herbal medicine to treat many diseases such as cancers. Triterpenes, polyphenols and anthraquinones are normally considered as the main constituents for its effects. In this study, eleven known triterpenes were isolated from the root of Actinidia chinensis., and were examined for its antiangiogenic activities. Their structures were elucidated by comprehensive spectroscopic methods, including IR, UV, HR-ESI-MS, and 1D and 2D NMR techniques. The eleven compounds are following: 2α,3α,19-trihydroxyurs-12-en-28-oic acid (1), 2α,3ß-dihydroxyurs-12-en-28-oic acid (2), 2α,3α,23-trihydroxyurs-12-en-28-oic acid (3), asiatic acid (4), ursolic acid (5), 2α,3ß,19,24-tetrahydroxyurs-12-en-28-oic acid (6), 2α,3ß,19-trihydroxyolean-12-en-28-oic acid (7), 2α,3α,24-trihydroxyolean-12-en-28-oic acid (8), oleanolic acid (9), 3ß-O-acetyloleanolic acid (10), 2α,23-dihydroxylmicromeric acid (11). All these compounds were evaluated with respect to their antiangiogenic activities utilizing the assays of human umbilical vein endothelial cells (HUVEC) proliferation and tube formation and Ursolic acid (used as control) and compounds 2, 3, 4, and 8 exhibited significant, dose-dependently, antiangiogenic activity in the tested concentration range. Our findings suggest that antitumor action of Actinidia chinensis Planch. is partly via inhibiting tumor angiogenesis by triterpenes, and compounds 2, 3, 4, and 8 as the novel potential antiangiogenic agents are worthy of further translational research.

Secolignans with antiangiogenic activities from Peperomia dindygulensis.

Two new secolignans, peperomins G and H (1 and 2, resp.), were isolated from the whole plant of Peperomia dindygulensis, together with five known secolignans, peperomin A (3), peperomin E (4), peperomin B (5), 2,3-trans-2-methyl-3-{(3-hydroxy-4,5-dimethoxyphenyl)[5-methoxy-3,4-(methylenedioxy)phenyl]methyl}butyrolactone (6), 2,3-cis-2-(hydroxymethyl)-3-{bis[5-methoxy-3,4-(methylenedioxy)phenyl]methyl}butyrolactone (7). Their structures and configurations were elucidated by spectroscopic methods including 2D-NMR techniques. Antiangiogenic effects of all compounds were evaluated using human umbilical vein endothelial cells (HUVEC) proliferation and tube-formation tests, with compounds 4 and 5 being active in the bioassay. Compounds 4 and 5 induced obvious cell toxicity to HUVEC with IC(50) values of 1.64±0.19 and 8.44±0.4 µM, respectively. Compounds 4 and 5 also exhibited significant HUVEC tube formation-inhibiting activity with IC(50) values of 3.13±0.09 and 6.24±0.12 µM, respectively.

Two unusual cases of intractable hyperthyroidism responsive to octreotide: Munchausen syndrome or not?

BACKGROUND: The effective treatment for patients with resistant hyperthyroidism is difficult. METHODS: In this case report with 4-year follow-up data, we present 2 unusual cases of hyperthyroidism that were unresponsive to almost all antithyroid treatments including total thyroidectomy, but both were controlled with octreotide. RESULTS: Cases 1 and 2 were both middle-aged women. They presented thyrotoxicosis with a low serum concentration of TSH and thyroidal radioactive iodine uptake (RAIU). The underlying causes, such as thyroiditis, metastatic thyroid cancer and struma ovarii were explored. Iodine-induced hyperthyroidism, particularly factitious hyperthyroidism was highly suspected, but there was no direct evidence to establish these diagnoses. In spite of good compliance, their thyrotoxicosis could not be controlled with large doses of PTU or MMI. ß-blocker, methylprednisolone, radio-iodine therapy and even thyroidectomy were all attempted and failed. Short-acting octreotide was first administered to case 1 and then to case 2. Thyroid function improved greatly within 3 days in both cases. The doses of octreotide were tapered down to twice a week with consistent efficacy. During the follow-up periods, case 1 required octreotide 0.1mg twice per week and case 2 is on thyroid replacement therapy due to hypothyroidism. The recurrences of hyperthyroidism in both cases were again rapidly controlled with the increased dose of octreotide in case 1 and re-started the usage of octreotide in case 2. CONCLUSIONS: The etiology of thyrotoxicosis in these 2 cases is not clear. In the absence of struma ovarii or wide-spread follicular thyroid cancer, factitious hyperthyroidism due to Munchausen syndrome should be considered first. The efficacy of the off-label use of octreotide in hyperthyroidism was highly effective (only) in these 2 cases.

Modulatory effect of anisodamine on airway hyper-reactivity and eosinophilic inflammation in a murine model of allergic asthma.

Anisodamine, a peripheral muscarinic receptor antagonist, is a naturally occurring atropine derivative that has been isolated, synthesized and characterized by scientists in China. In the present investigation, we evaluated the modulatory effects of anisodamine on airway hyper-reactivity and inflammation in a murine model of allergic asthma. Asthma model was induced successfully by ovalbumin. The activation of cells, airway eosinopilia, cytokine production, and airway function were examined. Our results collectively show that anisomanine could significantly suppress the accumulation of eosinophils into the airways and dramatically inhibited the histological changes in OVA-induced mice. Additionally, anisodamine could restore the Th1/Th2 balance in BALF by downregulating the level of Th2 cell-associated cytokine IL-4 (p<0.01) and upregulating the level of Th1 cell-associated cytokine IFN-γ (p<0.01). In addition, pretreatment with anisodamine also showed strong suppression of allergen-induced bronchial hyper-reactivity with maximum contraction decreasing from 0.45 ± 0.02 g to 0.28 ± 0.03 g (p<0.01). These results suggested the modulatory effects of anisodamine on Th1/Th2 balance by enhancing Th1-related and suppressing Th2-related parameters, as well as its potential application in airway hyper-reactivity and eosinophilic inflammation.

Efficacy and safety of natural acetylcholinesterase inhibitor huperzine A in the treatment of Alzheimer's disease: an updated meta-analysis.

The objective of this study was to provide an updated meta-analysis of the efficacy and safety of huperzine A (HupA) in Alzheimer's disease (AD). We searched for randomized trials comparing HupA with placebo in the treatment of AD. The primary outcome measures were mini-mental state examination (MMSE) and activities of daily living scale (ADL). Data were extracted from four randomized clinical trials and analyzed using standard meta-analysis and meta-regression methods. Oral administration of HupA for 8-24 weeks (300-500 microg daily) led to significant improvements in MMSE and ADL. The results of meta-regression showed that the estimated effect size of MMSE and ADL was increased over the treatment time. Most adverse events were cholinergic in nature and no serious adverse events occurred. Huperzine A is a well-tolerated drug that could significantly improve cognitive performance and ADL in patients with AD.

Is acupuncture beneficial in depression: a meta-analysis of 8 randomized controlled trials?

BACKGROUND: Depression is one of the most common mental health disorders. Acupuncture is a popular complementary and alternative medicine intervention suggested in the treatment of depression, but its effectiveness is uncertain. This updated meta-analysis was conducted to more precisely assess the beneficial effect of acupuncture in depression therapy. METHODS: The following databases were searched: MEDLINE, EMBASE, BIOSIS, Cochrane Central Register of Controlled Trials, and Chinese Scientific Journal Database. The following terms were used: acupuncture, acupressure, depression, depressive disorder, clinical trial, and randomized controlled trial. RESULTS: Eight small-randomized controlled trials comparing 477 subjects were included in the meta-analysis. Our results confirmed that acupuncture could significantly reduce the severity of depression, which was indicated by decreased scores of Hamilton rating scale for depression (HAMD) or Beck Depression Inventory (BDI). The pooled standardized mean difference of the 'Improvement of depression' was -0.65 (95% CI -1.18, -0.11; P=0.02) by random effect model. However, no significant effect of active acupuncture was found on the response rate (RR 1.32, 95% CI 0.83 to 2.10; P=0.25) and remission rate (RR 1.30, 95% CI 0.57 to 2.95; P=0.53). CONCLUSION: Although this meta-analysis might be discounted due to the low quality of individual trials, it supported that acupuncture was an effective treatment that could significantly reduce the severity of disease in the patients with depression. More full-scale randomized clinical trials with reliable designs are recommended to further warrant the effectiveness of acupuncture.

Antiproliferative effect of panaxynol on RASMCs via inhibition of ERK1/2 and CREB.

Panaxynol (PNN) occurs in many foods such as carrot, celery, and several reports have shown that it has neuritogenic and neuroprotective properties. In this study, we have investigated the antiproliferative effect and the mechanism of PNN on platelet-derived growth factor (PDGF)-BB-induced proliferation of rat aortic vascular smooth muscle cells (RASMCs). PNN significantly inhibited PDGF-BB-induced proliferation and DNA synthesis of RASMCs in a concentration-dependent manner. Flow cytometry analysis showed that PNN blocked the cell cycle progression at the G(1)/S phase. Preincubation of RASMCs with 9 microM PNN resulted in a significant inhibition of PDGF-BB-induced extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation expression and PDGF-BB-induced CREB phosphorylation expression. The results indicated that the inhibitory effect of PNN on the PDGF-BB-induced proliferation of RASMCs might be mediated by blocking phosphorylation of ERK1/2 and that of CREB.

Astragaloside IV from Astragalus membranaceus shows cardioprotection during myocardial ischemia in vivo and in vitro.

Astragaloside IV is the major active constituent of Astragalus membranaceus, which has been widely used for the treatment of cardiovascular diseases in China. However, the effects of astragaloside IV on myocardial ischemia and its mechanisms of action remain largely unknown. In this study, we have examined the effects of astragaloside IV on myocardial infarction and coronary flow in vivo and in vitro. The possible roles of its antioxidative and nitric oxide-inducing properties were also explored. Astragaloside IV significantly reduced infarct size in dogs subjected to coronary ligation in vivo. Astragaloside IV also improved post-ischemic heart function and ameliorated reperfusion arrhythmias in rat hearts in vitro. The cardioprotection of astragaloside IV was accompanied by a significant increase in coronary flow both in vivo and in vitro. The nitric oxide synthase inhibitor, Nomega-nitro- L-arginine methyl ester partially abrogated astragaloside IV's protective effect on heart function. Myocardial antioxidative enzyme superoxide dismutase activity increased with astragaloside IV administration. These data suggest the potential roles of antioxidative and nitric oxide-inducing properties of astragaloside IV in its protection from myocardial ischemia.

Panaxynol induces neurite outgrowth in PC12D cells via cAMP- and MAP kinase-dependent mechanisms.

Panaxynol, a polyacetylene ((3R)-heptadeca-1,9-diene-4,6-diyn-3-ol; syn. falcarinol), was isolated from the lipophilic fractions of Panax notoginseng, a Chinese traditional medicinal plant. In the present study, we reported the neurotrophic effects of panaxynol on PC12D cells and mechanism involved in neurite outgrowth of the cells. Panaxynol could morphologically promote neurite outgrowth in PC12D cells, concentration-dependently reduce cell division and up-regulate molecular marker (MAP1B) expression in PC12D cells. Panaxynol induces the elevation of intracellular cAMP in PC12D cells. The neurite outgrowth in PC12D cells induced by panaxynol could be inhibited by the protein kinase A inhibitor RpcAMPS and by MAP kinase kinase 1/2 inhibitor U0126. These observations reveal that panaxynol could induce the differentiation of PC12D cells in a process similar to but distinct from that of NGF and the panaxynol's effects were via cAMP- and MAP kinase-dependent mechanisms.

Activity and QSAR study of baogongteng A and its derivatives as muscarinic agonists.

Baogongteng A (BGT-A), a naturally occurring tropane muscarinic agonist isolated from Chinese medicinal plant, exhibits a bioactive effect different from those of many tropane alkaloids that are muscarinic antagonists. A series of racemic derivatives of BGT-A was synthesized to study the structure-activity relationships (SAR). To explore further the SAR in this series and to ultimately design muscarinic agonists for drug development, a Comparative Molecular Field Analysis (CoMFA) was performed. The values of the leave-one-out cross-validated correlation coefficient q2 and the conventional correlation coefficient r2 for the model are 0.613 and 0.965, respectively. The regression analysis of the data indicated that the steric effect of N-substituted group on tropane of analyzed compounds critically affected the agonistic activity to muscarinic receptors.