I had a dreadful feeling of deja vu before finding out this patent referenced the structural analogs I skimmed over earlier today lol.
I'll make a separate thread for (-)clausenamide to avoid crossing the streams.
http://www.google.co...1589002A1?cl=en
Bioactive Compounds from Chinese Medicinal Plants
Xiao-Jiang HaoThe Sate Key Laboratory of Phytochemistry and Plant Resources in West China, KunmingInstitute of Botany, The Chinese Academy of Sciences, Heilongtan, Kunming, Yunnan 650204,China [E-mail: xjhao@hotmail.com or yshen@public.km.yn.cn]The chemical investigations on Spiraea japonica and its varieties have led to the report of 10new atisane-type diterpenoids including two new glycosides and more than 30 new diterpenealkaloids of atisine- and hetisine-type. Some of those alkaloids such as spiramine Qsignificantly inhibited rabbit platelet aggregation induced by PAF and AA in vitro and exvivo, and others like spiramine T exhibited protective effects on cerebral ischemia-reperfusioninjury in gerbils. Parts of semisynthetic sulfur-containing atisane-type diterpenoids showedneuroprotective effects on cortical neurons. Some O-terpenoidal coumarins isolated fromplants of the genus Clausena exhibited neuroprotective effects as well.Nootropic agent, aniracetam was developed in Europe, and entered market this year.Clausenamide was a nootropic drug discovered from plant by Beijing Institute of MateriaMedica. Our group designed and synthesized a series of molecules based on the studies onaniracetam and clausenamide. After screening, KMBZ-009 was found to be more active thananiracetam and clausenamide, and is eight times more active than aniracetam.The Third International Symposium for Chinese Medicinal Chemists, Hong Kong, 28-31 December 2002
Yu, S. M.; Cai, J. X., 2001: Effects of KMBZ-009 and aniracetam on transmitter amino acids release induced by transient cerebral ischemia/reperfusion in awake gerbil hippocampus A brain microdialysis in vivo. Society For Neuroscience Abstracts. 27(1): 558Our previous studies showed that aniracetam and KMBZ-009, a new 3,5-bisubstituent pyrolidone analog, obviously improved learning and memory deficits in TCIR treated gerbils, and delayed neronal death (DND) evoked by TCIR in their hippocampus was reversed by KMBZ-009 and aniracetam. In this study, by means of brain microdialysis and RP-HPLC, the effects of KMBZ-009 and aniracetam on transmitter amino acids release following TCIR in awake gerbil hippocampus were detected in vivo. Microdialysis probes were placed in the hippocampus of aged gerbils (22-24 months old). TCIR was induced by clamping bilateral common carotid artery (10min) and reperfusion (3h). The results showed that after TCIR 10min, the levels of extracellular glutamate (GLU), aspartate (ASP), GABA, glycine (GLY), beta-alanine (beta-ALA) and taurine (TAU) increased 8-, 7-, 4-, 2-, 3- and 2-fold over baseline respectively. After 30min, all amino acids returned to normal. After p.o. KMBZ-009 (10mg/kg) or aniracetan (100mg/kg) at 1h prior to TCIR, GLU and ASP decreased 74%, 56% or 68%, 54% of peak (p<0.01), GLY and beta-ALA also decreased (p<0.05), but GABA slightly increased (p>0.05), TAU increased 2.5- or 1.6-fold of peak (p=0.02) and retained 2- or 1-fold during 30-180min. It suggested that the elevation of TAU, GABA, reduction of excitatory amino acids (GLU, ASP) evoked by KMBZ-009 or aniracetam in hippocampus of gerbils via TCIR treatment might relate to the neuroprotective effects of KMBZ-009 or aniracetam on DND in the hippocampus.
http://eurekamag.com...1/034811792.php
Part 1. Mechanism study on the anti-stress-like and anti-depressant-like effects of KMBZ-009. Although the acute response to stress (e.g., heightened cognition) is an adaptive mechanism, excessive stress, in particular uncontrollable stress induces many psychological and physiological problems. Specially, hippocampus- or prefrontal cortex-dependent learning and memory are dramatically impaired by stress. And its mechanism was associated with stress-induced release changes of stress hormone (corticorsterone etc.) and neurotransmitters and deficit of synaptic plasticity (such as LTP and LTD). Many studies have proved that several psychiatric disorders such as depression were related to stress, and the functions of HPA axis and monoamine neurotransmitters system were its underline mechanisms. Previous works of our Lab have proved that KMBZ-009 (a novel compound of pyrrolidone derivatives. It was named phenchlobenpyrrone) changed neurotransmitters release in brain by modulating intracellular Ca2+ concentration, and as a consequence, the higher functions of the brain such as learning and memory were changed by KMBZ-009. However, they are unclear so far whether KMBZ-009 ameliorates stress-induced memory deficit and whether it has anti-depressant-like effect. In the present study, using Morris water maze tasks, operant box paradigm, forced-swim test, patch-clamp in vitro recording and in vivo electrophysiological techniques, we study the effect of KMBZ-009 on acute stress-induced spatial memory deficit and depressive behaviors, as well as its underlining mechanisms. The data showed that acute inescapable stress or a dose of exogenous corticosterone (CORT, 10 mg kg-1) significantly decreased the search times in the target quadrant during retest period. Protective doses of KMBZ-009 (20, 40 mg kg-1), administrated 30 min before acute inescapable stress or CORT injection, abolished memory retrieval deficits seen in untreated rats. Memory is believed to dependent on synaptic plasticity. Here, it was showed that long-term depression (LTD) in the CA1 region of the hippocampus in vivo was facilitated by acute inescapable stress, sub-acute footshock stress and CORT. Pretreatment with KMBZ-009 (10, 20, 40 mg kg-1) inhibited that facilitation. In addition, acute inescapable stress also blocked induction of hippocampal long-term potentiation (LTP), pretreatment with 20 mg kg-1 KMBZ-009 30 min before acute inescapable stress normalized hippocampal LTP induction. Immunoassay results revealed an expected stress-induced CORT increase, and stress-increased CORT level was significantly diminished by KMBZ-009 (10, 20 and 40 mg kg-1) administration. Moreover, KMBZ-009 modulates the functions of AMPARs and GABAARs. The results showed that KMBZ-009 had no effect on NMDARs-mediated EPSCs, but it increased the amplitude of AMPARs-mediated EPSCs without changing of its kinetics at 400μmol L-1 concentration. KMBZ-009 did not change the amplitude of GABAARs-mediated IPSCs, however, the decay time of GABAARs-mediated IPSCs were prolonged by KMBZ-009 at the dose of 100μ mol L-1. For GABAARs-mediated miniature IPSCs (mIPSCs), the decay time was also significantly prolonged by KMBZ-009 (100μmol L-1), but it had no effects on the rise time, amplitude and frequency of mIPSCs. The effect of KMBZ-009 on both excitatary and inhibitary currents contributes maintaining normal functions of pyramidal neurons in hippocampus when underdoing stress. Exposure to stress has been linked to the pathophysiology of depression and anxiety disorders. The ameliorating effect of KMBZ-009 on stress suggests that it may be useful in clinical treatment for stress and stress-related psychiatric disorders such as PTSD, depression/anxiety. Data showed that Treatments of animals with KMBZ-009 (5, 10,20mg kg -1 p.o.) dose-dependent reduced the time of immobility and increased the latency to immobility of mice in FST, without any significant effect on locomotor activity of mice. The dose of 20 mg kg -1 of KMBZ-009 significantly increased the reinforcement rate and decreased the response rate of rats in DRL-72s. DL-propranolol (2 mg kg -1 i.p.; a β-adrenoceptor antagonist) and phentolamine (1 mg kg -1 i.p.; an α-adrenoceptor antagonist) significantly attenuated the KMBZ-009- induced antidepressant-like effect in FST. These data suggests that KMBZ-009 may possess an antidepressant-like effect, mediated by increase of brain norepinephrine. Part 2. KMBZ-009 attenuates oxidative stress-induced deficiency of neuron viability, mitochondria potential and hippocampal long-term potentiation of mice in vitro It is known that the free radicals are involved in neurodegeneration and the cognitive dysfunction, as seen in Alzheimer's disease (AD) and aging. Aniracetam, a compound of pyrrolidone derivatives, was reported to antagonize the ischemia-induced astrocytes degeneration at least in part by reducing the ROS production. Primary cell cultures and electrophysiological technique were used to examine the protective effects of aniracetam or KMBZ-009 against H2O2-induced toxicity to neuron viability, mitochondria potential and hippocampal long-term potentiation (LTP). Data showed that H2O2 exposure impaired the viability of neurons, reduced mitochondria potential and decreased LTP in the CA1 region of hippocampus. These deficient effects were significantly rescued by pre-treatment with aniracetam or KMBZ-009.
http://159.226.149.4.../6104?mode=full
KIB hosted by the Kunming Institute of Botany, Kunming Institute of Zoology, Shanghai and other units participating in the development of drugs to improve memory impairment for the study of various targets a class of innovative medicines KMBZ-009, after a 10-year study, recently completed all preclinical studies, clinical studies reporting data has been basically finishing is completed, and will soon report to the Food and Drug Administration. The project has received pre-clinical research topics Ministry of Science 1035, 863 topics, National Outstanding Youth Science Foundation, the National Natural Science project, the hospital 1995 and fifteen major project topics, Yunnan Key project funding. The project is in pre-clinical studies of new compounds for the study of different types, in order to improve a variety of memory impairment as a kind of innovative drug research objectives. Its technical features and innovations that: new chemical structure: nootropics and foreign development different compound of formula KMBZ-009 uses not covered by domestic and foreign patent applications, so the formula is authorized applicants national invention patent claims protected content.Synthesis: Synthesis of Compound of new synthetic methods for the new structure of the intermediate, the synthesis of the protected content and intermediates belong patent claims. After several years of improvement, the current process is conducive to large-scale, good reproducibility. Completed a research activity screening and QSAR system, has synthesized more than 100 kinds of new compounds, calcium antagonistic activity of smooth muscle cells with calcium antagonistic activity of nerve cells as a preliminary evaluation to study the types of substituents, substitution position The relative and absolute configuration configuration activity of the findings so far, KMBZ-009 is still the best choice. Found KMBZ-009 and its derivatives are a class of highly selective neuronal calcium antagonists. Has the effect of improving the various memory disorders, various experimental results to improve memory in animal models indicate that the drug potency KMBZ-009 was significantly better than Aniracetam with oral rapid onset of absorption, through the blood-brain barrier, high degree of safety. The study has applied for four patents, three of which have been authorized. Since the study has not yet applied for international patents, therefore, to ensure confidentiality, not published any papers. The drug is a new mechanism of pharmacological drugs, in particular to improve memory disorders, anti-senile dementia, improve learning and memory and other indications of normal. This medicine is in full compliance with the relevant provisions of the Chinese Pharmacopoeia, quality and stability. Thus, the drug is a very worthwhile conducting clinical trials of new drugs to enhance memory function for the treatment of senile memory impairment, vascular dementia and senile dementia have good prospects and great social significance.
http://www.dxy.cn/bb...d/652034#652034
Synthesis and novel calcineurin antagonist activity pyrrolidone cells progressHao Xiaojiang researcher from the Kunming Institute of Botany, chaired Yunnan Natural Science Foundation of China, "Synthesis of novel pyrrolidone calcineurin antagonist activity of cells", on November 16 passed by the Yunnan Provincial Science and Technology Department of the Group of Experts knot acceptance.Yunnan Provincial Science and Technology Department invited experts Kunming precious metals, Yunnan College of Medicine, College of Yunnan, Yunnan drugs, and Kunming, Yunnan Institute for Drug Control Branch and other units of the composition of the expert group, in charge of the project who heard the report after the formation of the following comments: the project team has presided over the development of innovation-based proprietary natural medicine KMBZ-009 to work on a class, according to the requirements of Yunnan Natural Science Foundation of Science and Technology Department of the project contract, after four years of hard work, a lot of research done work, has synthesized a variety of 90-substituted pyrrolidone derivatives, including mono-substituted, 4,5 - disubstituted, 3,4,5 - tri-substituted, N-substituted alkyl, N-acyl, N-carboxy-substituted and KMBZ-009 in vivo metabolites type, wherein the disubstituted derivatives include the cis and trans isomers. Finished split KMBZ-009 optical isomer was measured in X-crystal diffraction, a synthetic derivative of the measured calcium antagonistic activity of vascular smooth muscle, measured calcium compound selected portions of the antagonistic activity of nerve cells, the initial configuration activity relationship studies showed that: replace pyrrolidone is highly selective neuronal calcium antagonists, calcium antagonistic activity on vascular smooth muscle cells and nerve calcium antagonistic relationship between the presence of active strength; 3,4,5 - tri-substituted and 4,5 - calcium di-substituted derivatives of the antagonistic activity of the strongest mode is the best mode of the structure of the target molecule drug design; absolute configuration had no significant effect on the activity. The use of comparative molecular field method, computer-aided design, 30 compounds were studied QSAR. Use tips CoMFA model designed two new compounds P1 and P2, and their activity was predicted, the results showed that there were higher than the compound. The study has been three national invention patents. Acceptance of the view that the Group of Experts, the project studies the major innovations are: the establishment of a vascular smooth muscle - nerve cell calcium antagonist activity evaluation system; newly discovered three highly active compounds substituted pyrrolidone; established substituted pyrrolidone structure optimization model.Group of Experts also believe that the acceptance opinion, KMBZ-009 is a new structure type of innovative drugs, is currently in preclinical studies have been completed, the project is carried out on the basis of structure-activity relationship studies on a series of derivatives, not only in the discovery of new active substances and strong breakthrough, but also through the establishment of a computer-aided design optimization model, expanding the scope of intellectual property protection, and lay a good foundation for the future of drug design and development series. The study is based drugs to independent innovation, combined with chemical synthesis - biological activity - computer-aided design of modern research model, is carried out with our own intellectual property rights of innovative drug discovery phase of the study's successful model. Acceptance Group agreed that the acceptance of the project by concluding comprehensive evaluation rating of "excellent." Also proposed to speed up the application as early as possible in the pharmaceutical industry.
