Isovaleramide is an active principle on central nervous system from Valeriana pavonii, as an anticonvulsant.Target：in vitro: Isovaleramide (300 μM) exhibits a 42% of inhibition of the binding of 3H-FNZ to its sites.in vivo: Isovaleramide at 100 mg/Kg, p.o, evidences a 90% index protection against the maximal electroshock seizure in mice (MES).
Alfuzosin hydrochloride is an α1 adrenergic receptor antagonist used to treat benign prostatic hyperplasia (BPH).Target: α1 adrenergic receptorAlfuzosin, a new quinazoline derivative, acts as a selective and competitive antagonist of alpha 1-adrenoceptor-mediated contraction of prostatic, prostatic capsule, bladder base and proximal urethral smooth muscle, thereby reducing the tone of these structures. Consequently, urethral pressure and resistance, bladder outlet resistance, bladder instability and symptoms associated with benign prostatic hyperplasia are reduced. A limited range of clinical studies have shown oral alfuzosin to be more effective than placebo (in studies of < or = 6 months duration), to have sustained effects on long term administration (< or = 30 months), and to be comparable with the alpha 1-adrenoceptor antagonist prazosin, in the symptomatic treatment of benign prostatic hyperplasia.Oral alfuzosin 7.5 to 10 mg/day in divided doses appears to be a promising first-line agent for symptomatic treatment of noncomplicated mild to moderate benign prostatic hyperplasia in patients with a high dynamic component to their obstruction. In addition, alfuzosin offers an alternative to prostatectomy (the current 'gold standard') in patients who require surgery but are unfit for this treatment, and in patients requiring symptomatic relief while awaiting surgery.
Pemetrexed disodium is a novel antifolate that inhibits the folatedependent enzymes thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase with Kis of 1.3, 7.2, and 65 nM, respectively.
Mesaconitine is the main active component of genus aconitum plants.IC50 value:Target: in vitro: In HUVECs, 30 microM mesaconitine increased the [Ca(2+)](i) level in the presence of extracellular CaCl(2) and NaCl, and the response was inhibited by KBR7943. Mesaconitine increased intracellular Na(+) concentration level in HUVECs. The [Ca(2+)](i) response by mesaconitine was inhibited by 100 microM D-tubocurarine [1]. Mesaconitine at 30 microM inhibited 3 microM phenylephrine-induced contraction in the endothelium-intact, but not endothelium-denuded, aortic rings [2]. MA promoted the alpha-MT-induced decrease in NE levels in hippocampus, medulla oblongata plus pons and spinal cord [3].
Guvacine hydrochloride is an alkaloid from the nut of Areca catechu, acts as an inhibitor of GABA transporter, and dispalys modest selectivity for cloned GABA transporters with IC50s of 14 μM (human GAT-1), 39 μM (rat GAT-1), 58 μM (rat GAT-2), 119 μM (human GAT-3), 378 μM (rat GAT-3), and 1870 μM (human BGT-3).
Dehydrocorydaline (13-Methylpalmatine) is an alkaloid isolated from traditional Chinese herb Corydalis yanhusuo W.T. Wang. Dehydrocorydaline regulates protein expression of Bax, Bcl-2; activates caspase-7, caspase-8, and inactivates PARP.
Trabectedin (Ecteinascidin-743 or ET-743) is a novel antitumour agent of marine origin with potent antitumour activity both in vitro and in vivo.IC50 Value: 0.1-3.7 nM (breast cancer cell lines) [1]Target: Apoptosis inducer; Anticancerin vitro: Trabectedin induced cytotoxicity and apoptosis in both breast cancer cells in a time and concentration-dependent manner. The expression levels of the death receptor pathway molecules, TRAIL-R1/DR4, TRAIL-R2/DR5, FAS/TNFRSF6, TNF RI/TNFRSF1A, and FADD were significantly increased by 2.6-, 3.1-, 1.7-, 11.2- and 4.0-fold by trabectedin treatment in MCF-7 cells. However, in MDA-MB-453 cells, the mitochondrial pathway related pro-apoptotic proteins Bax, Bad, Cytochrome c, Smac/DIABLO, and Cleaved Caspase-3 expressions were induced by 4.2-, 3.6-, 4.8-, 4.5-, and 4.4-fold, and the expression levels of anti-apoptotic proteins Bcl-2 and Bcl-XL were reduced by 4.8- and 5.2-fold in MDA-MB-453 cells [2]. In vitro treatment with noncytotoxic concentrations of trabectedin selectively inhibited the production of CCL2, CXCL8, IL-6, VEGF, and PTX3 by MLS primary tumor cultures and/or cell lines [3].in vivo: A xenograft mouse model of human MLS showed marked reduction of CCL2, CXCL8, CD68+ infiltrating macrophages, CD31+ tumor vessels, and partial decrease of PTX3 after trabectedin treatment [3]. The MTD of trabectedin was 700 microg/m(2) due to dose-limiting neutropaenia and the RDs in the previously treated/untreated patients were 500 and 600 microg/m(2), respectively. Most common toxicities were nausea/vomiting (67%), asthenia/fatigue (55%) and reversible ASAT/ALAT elevation (51%) [4]. Toxicity: Most common toxicities were nausea/vomiting (67%), asthenia/fatigue (55%) and reversible ASAT/ALAT elevation (51%) [4].Clinical trial: A Study to Assess the Potential Effects of Rifampin on the Pharmacokinetics of Trabectedin in Patients With Advanced Malignancies. Phase 1/2
Catharanthine inhibits nicotinic receptor mediated diaphragm contractions with IC50 of 59.6 μM.Target: nAChRCatharanthine evokes a concentration-dependent attenuation of carbachol responses in the rat ileum preparation, producing rightward curve displacements and decreases in maximal agonist responses. The mixture of serpentine, plus ajmalicine and catharanthine reveals a concentration-dependent inhibitory effect of acethylcholinesterase (AchE), with an IC50 at ca. 2.25 μg/Ml [1]. Catharanthine can induce the self-association of tubulin into linear indefinite polymers with an efficacy that is 75% that of vinblastine or vincristine. Catharanthine binds to tubulin alpha-beta dimer with binding constant of 2.8 mM [2]. Catharanthine stimulates release of amylase from pancreatic fragments and to cause extensive degranulation of pancreatic acinar cells with accumulation of membrane material in the Golgi region. Catharanthine induces a delayed release of Ca2+ from prelabeled pancreatic fragments as compared to bethanechol [3]. Catharanthine inhibits epibatidine-induced Ca(2+) influx in TE671-α, -β, -γ, -δ cells in a noncompetitive manner with similar potencies IC50 of 17 mM-25 mM. Catharanthine inhibits [3H]TCP binding to the desensitized Torpedo AChR with higher affinity compared to the resting AChR. Catharanthine enhances [3H]cytisine binding to resting but activatable Torpedo AChRs, suggesting desensitizing properties [4].
Doxazosin(UK 33274) is a quinazoline-derivative that selectively antagonizes postsynaptic α1-adrenergic receptors.Target: Adrenergic ReceptorDoxazosin is a long-lasting inhibitor of α1-adrenoceptors that is widely used to treat benign prostatic hyperplasia and lower urinary tract symptoms [1]. doxazosin may have a direct inhibitory effect on cholesterol synthesis independent of the LDL receptor. The inhibition of cholesterol synthesis by doxazosin may cause cells to compensate by upregulating the LDL receptor, thereby increasing the importation of lipoprotein cholesterol and reducing LDL cholesterol in the medium [2]. Doxazosin monotherapy was effective in eight of 12 patients (66.7%), and combined therapy with a beta-blocker was effective in 11 of 12 patients (91.7%). The mean pulse rate remained constant throughout therapy. Adverse reactions were minor and transient and occurred in only three patients. Urinary and plasma catecholamine levels tended to decrease or remained unchanged during doxazosin therapy [3].Clinical indications: Hypertension; Prostate hyperplasiaFDA Approved Date: February 22, 2005Toxicity: Symptoms of overdose include hypotension
Tropisetron(SDZ-ICS 930) is a selective 5-HT3 receptor antagonist and α7-nicotinic receptor agonist with an IC50 of 70.1 ± 0.9 nM for 5-HT3 receptor. IC50 value: 70.1 ± 0.9 nM [1]Target: 5-HT3 receptorin vitro: Tropisetron specifically inhibited both IL-2 gene transcription and IL-2 synthesis in stimulated T cells. tropisetron inhibited both the binding to DNA and the transcriptional activity of NFAT and AP-1. We also observed that tropisetron is a potent inhibitor of PMA plus ionomycin-induced NF-(kappa)B activation but in contrast TNF(alpha)-mediated NF-(kappa)B activation was not affected by this antagonist [2]. Tropisetron prevents the phosphorylation and thus activation of the p38 MAPK, which is involved in post-transcriptional regulation of various cytokines [3].in vivo: Two different doses of tropisetron (5 and 10 mg/kg) or vehicle were administered intraperitoneally 30 min before pMCAO. Neurological deficit scores, mortality rate and infarct volume were determined 24 h after permanent focal cerebral ischemia [4].
Sinapine is an alkaloid from seeds of the cruciferous species which shows favorable biological activities such as antioxidant and radio-protective activities.
Cephalotaxine is an antiviral as well as antitumor agent.
Tomatidine acts as an anti-inflammatory agent by blocking NF-κB and JNK signaling.
Pipofezine(Azafen or Azaphen) is a potent inhibitor of the reuptake of serotonin. IC50 Value: Target: SSRIsPipofezine is a tricyclic antidepressant (TCA) approved in Russia for the treatment of depression. In addition to its antidepressant action, pipofezine has sedative effects as well, indicating antihistamine activity.
6-Chloropurine is a building block in chemical synthesis. Intermediate in the preparation of 9-alkylpurines and 6-rnercaptopurine. Antitumor activities[1].
Oxcarbazepine inhibits the binding of [3H]BTX to sodium channels with IC50 of 160 μM and also inhibits the influx of 22Na+ into rat brain synaptosomes with IC50 about 100 μM.Target: Sodium ChannelOxcarbazepine is an antiepileptic drug with a chemical structure similar to carbamazepine, but with different metabolism. Oxcarbazepine is rapidly reduced to 10,11-dihydro-10-hydroxy-carbazepine (monohydroxy derivative, MHD), the clinically relevant metabolite of oxcarbazepine. MHD has (S)-(+)- and the (R)-(-)-enantiomer [1]. Oxcarbazepine (oxcarb) 600 and 900 mg (2360 and 3540 mumol) was taken by 3 volunteers (2 female, 1 male; 45-67 kg; age 22-34 years) after an overnight fast. Blood, saliva and urine were collected for the next 72 h for assay of oxcarb, 10,11-dihydro-10-hydroxy-carbamazepine (OHcarb), and 10,11-dihydro-trans-10,11-dihydroxy-carbamazepine (diol). Oxcarb reached a maximum level of about 1 microgram/ml (3.93 mumol/l) within 1 h and dropped below the detection limit (0.1 microgram/ml = 0.39 mumol/l) within 3 h. The active metabolite OHcarb appeared in the blood before oxcarb and reached the higher maximum level of 7.4 microgram/ml (29 mumol/l) after 7 h [2]. Clinical indications: EpilepsyToxicity: Isolated cases of overdose with oxcarbazepine have been reported. The maximum dose taken was approximately 24,000 mg. All patients recovered with symptomatic treatment.
(-)-Securinine is plant-derived alkaloid and also a GABAA receptor antagonist.
Flaconitine is isolated from the ammonium hydroxide wetted root of A.szechenyianum Gay. Flaconitine is considered to be a NF-κB inhibitor.
Peiminine(Verticinone; Raddeanine) is a natural compound with anti-inflammatory activity.IC50 value:Target:Peiminine and DXS significantly reduced alveolar inflammation and pulmonary interstitial inflammation in rats with bleomycin-induced lung injury. peiminine inhibits lung inflammation and pulmonary fibrosis in a rat model of bleomycin-induced lung injury, by reducing circulating IFN-γ levels and inhibiting signal transduction pathways involving TGF-β, CTGF, ERK1/2, NF-κB and FasL.
Theophylline is a nonselective phosphodiesterase (PDE) inhibitor, adenosine receptor blocker, and histone deacetylase (HDAC) activator.
Cefaclor, is a second-generation cephalosporin antibiotic used to treat certain infections caused by bacteria such as pneumonia and infections of the ear, lung, skin, throat, and urinary tract.Target: AntibacterialCefaclor belongs to the family of antibiotics known as the cephalosporins (cefalosporins). The cephalosporins are broad-spectrum antibiotics that are used for the treatment of septicaemia, pneumonia, meningitis, biliary tract infections, peritonitis, and urinary tract infections. The pharmacology of the cephalosporins is similar to that of the penicillins, excretion being principally renal. Cephalosporins penetrate the cerebrospinal fluid poorly unless the meninges are inflamed; cefotaxime is a more suitable cephalosporin than cefaclor for infections of the central nervous system, e.g. meningitis. Cefaclor is active against many bacteria, including both Gram-negative and Gram-positive organisms.Cefaclor is frequently used against bacteria responsible for causing skin infections, otitis media, urinary tract infections, and others. The following represents MIC susceptibility data for a few medically significant microorganisms. Cefaclor is passed into the breast milk in small quantities, but is generally accepted to be safe to take during breastfeeding. Cefaclor is not known to be harmful in pregnancy. Cefaclor has also been reported to cause a serum sickness-like reaction in children.
Ligustrazine (hydrochloride) is a natural product.IC50 value:Target:In vitro: Ligustrazine hydrochloride displayed a protection effect on injured ECV304 cells, NOS and NO formation were significantly increased compared with the model group [1].In vivo:
Reserpine hydrochloride is an inhibitor of the vesicular monoamine transporter 2 (VMAT2).
Sulfapyridine(Dagenan) is a sulfonamide antibacterial.Target: AntibacterialSulfapyridine(Dagenan) is a sulfonamide antibacterial. Sulfapyridine is not prescribed for the treatment in humans any more. However, it may be used to treat Linear IgA Disease. It is a good antibacterial drug, but its water solubility is very dependent on PH. Thus, there is a risk of crystallization within the bladder or urethra, which could lead to pain or blockage. The drug sulfasalazine is structurally one molecule of mesalamine linked to one molecule of Sulfapyridine with an azo bond [1].
Talipexole (B-HT920) is a dopamine agonist that has been proposed as an antiparkinsonian agent.Target: Dopamine ReceptorB-HT920 is a selective alpha 2-adrenoceptor agonist. The effects of B-HT920 have been specified using the alpha-adrenergic antagonists yohimbine and prazosin and the dopamine antagonist haloperidol. Yohimbine could not antagonize any of the actions of B-HT920. Pretreatment with prazosin showed a decrease in the loss of body weight caused by B-HT920, while pretreatment with yohimbine showed that B-HT920 induced an increased loss in body weight. These data suggest that B-HT920 under certain conditions exerts dopamine-agonistic actions in stimulating locomotor activity and alpha 1-adrenergic actions in inducing salivation and enhanced loss of body weight [1]. Concomitant treatment with talipexole, an anti-parkinsonian drug, inhibited MPTP-induced autolysis and individual death in a concentration-dependent manner. Pramipexole showed a similar protective effect. In addition, post-treatment with talipexole at 1 hr after MPTP completely inhibited MPTP-induced individual death. Although MPTP treatment caused 30% of the planarians to undergo autolysis and individual death within 12 hr, post-treatment with talipexole even at 12 hr completely rescued the remaining 70% of the planarians from death. These results suggest that the MPTP-treated planarian may be useful as a novel parkinsonian model in which talipexole has a protective effect even in the case of post-treatment [2].
Vincristine sulfate is an antitumor vinca alkaloid which inhibits microtubule formation in mitotic spindle, resulting in an arrest of dividing cells at the metaphase stage. It binds to microtubule with a Ki of 85 nM.
(S)-Nornicotine is a metabolite of nicotine.
Castanospermine inhibits all forms of α- and β-glucosidases, especially glucosidase l (required for glucoprotein processing by transfer of mannose and glucose from asparagine-linked lipids).target：α- and β-glucosidases.IC 50: 1.2 uM [2] in vitro :Castanospermine, [(1 S,6S,7R,8R,8aR)-1 ,6,7,8-tetrahydroxyoctahydroindolizine]is a potent and specific inhibitor of mammalian and plant α-and β-D-glucosidases in vitro [1] in vivo: Experiments in vivo with castanospermine, an inhibitor of the glucosidases that convert protein N-linked high mannose carbohydrates to complex oligosaccharides, resulted in significant inhibition of tumor growth in nude mice.[3]
Pefloxacin is a an antibacterial agent and prevents bacterial DNA replication by inhibiting DNA gyrase (topoisomerse)Target: DNA gyrasePefloxacin is a synthetic chemotherapeutic agent used to treat severe and life-threatening bacterial infections. Pefloxacin is commonly referred to as afluoroquinolone (or quinolone) drug and is a member of the fluoroquinolone class of antibacterials. It is an analog of norfloxacin. It is a synthetic fluoroquinolone, belonging to the 3rd generation of quinolones. Pefloxacin is extensively prescribed in France. Pefloxacin has not been approved for use in the United States.The bactericidal action of pefloxacin results from interference with the activity of the bacterial enzymes DNA gyrase and topoisomerase IV, which are needed for the transcription and replication of bacterial DNA. DNA gyrase appears to be the primary quinolone target for gram-negative bacteria. Topoisomerase IV appears to be the preferential target in gram-positive organisms. Interference with these two topoisomerases results in strand breakage of the bacterial chromosome, supercoiling, and resealing. As a result DNA replication and transcription is inhibited.
Fumitremorgin C is a potent and selective ABCG2/BRCP inhibitor.