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991.
《Expert opinion on drug discovery》2013,8(11):1255-1258
Drug abuse and addiction to licit and illicit drugs constitute an almost worldwide health and socioeconomic problem. This problem can be addressed in a number of ways. As far as pharmaceutical development and drug therapy is concerned, abuse-deterrent formulations (ADF), substitution therapies, antagonist therapies, aversion therapies, and diverse novel approaches can be considered. ADF (or tamper-resistant formulations) are an important step towards preventing the abuse of medically used drugs, such as strong opioid analgesics, and some drug treatments are well established, such as substitution therapy in opioid dependence with methadone and buprenorphine. Nevertheless, a large medical need remains, and drugs that effectively curb opioid or psychostimulant addiction by promoting abstinence and preventing relapse have yet to be developed. Many different targets and mechanisms are currently being considered in preclinical research, but apart from repurposing or reformulating already known drugs, very little clinical development is currently ongoing. It is hoped that at least a few of the investigated approaches (e.g., various glutamate and GABA receptor modulators, nociceptin/orphanin FQ peptide receptor agonists, or histamine H3 receptor antagonists) reach the stage of clinical development and eventually reach regulatory approval. 相似文献
992.
《Expert opinion on therapeutic patents》2013,23(10):1357-1359
Several substituted 2,3-dioxo-1,2,3,4-tetrahydroquinoxaline-5-ylmethyl)- amino-alkylphosphonic acids are disclosed as excitatory amino acid antagonists. No specific biological data are reported and compounds are claimed to exhibit an especially strong affinity for the α-amino-3- hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and/or kainate binding sites, and a less strong affinity for the glycine binding sites of the N-methyl-D-aspartic (NMDA) receptor. Over 100 compounds are specifically claimed, 77 are characterised and specific synthetic methods for 10 compounds are presented. The compounds can be used in the preparation of medicament for the treatment of pathological conditions that are responsive to blocking of AMPA, kainate and/or glycine binding sites of the NMDA receptor. 相似文献
993.
《Expert opinion on therapeutic patents》2013,23(1):75-98
There are now numerous drugs in advanced stages of clinical testing as potential antipsychotics. The major focus of development of antipsychotics is serotonin (5-HT)2A antagonism, based on the hypothesis that this property is a critical facet of the pharmacology of clozapine and risperidone. These drugs have been found to exhibit relatively potent 5-HT2A antagonism compared to their dopamine D2 antagonistic effects. A large number of other antipsychotics with a similar 5-HT2A/D2 profile have been identified. In general, these compounds have minimal cataleptic effects at doses that block dopamine receptor agonist-induced behaviour, and have highly selective effects on mesolimbic dopamine neurones. Because they differ in relative potency as antagonists of a variety of other key receptors (e.g., D1, D2, D3, D4, D5, 5-HT2A, 5-HT2C, 5-HT6, 5-HT7, M1 and α1-adrenoceptors), it is likely that these compounds will have significantly different side effects and efficacy profiles (multi-acting receptor targeted agents [MARTA]). Some may be effective in treating negative symptoms and improving cognitive dysfunction. The potential usefulness of N-methyl-D-aspartate (NMDA) receptor agonists for schizophrenia is limited by possible epileptogenic or neurotoxic side effects. In this respect, ligands at strychnine-insensitive glycine binding sites of the NMDA receptor ion channel complex and metabotropic glutamate receptors (mGluR) are expected to have relatively few side effects. A novel sigma1 receptor antagonist appears to be of particular interest based upon its ability to block the behavioural effects of phencyclidine (PCP). The close relationship between some neuropeptides, such as cholecystokinin and neurotensin, and dopaminergic systems in the brain is sufficient to sustain interest in these apart from the tantalising possibility of mediation by a neuropeptide system of some of the psychopharmacology of schizophrenia. 相似文献
994.
《Expert opinion on therapeutic patents》2013,23(4):393-408
Introduction: The design and development of small molecule negative allosteric modulators (NAMs) of the metabotropic glutamate receptor subtype 5 (mGlu5) has been an area of intense interest for over a decade. Potential roles have been established for mGlu5 NAMs in the treatment of diseases such as pain, anxiety, gastroesophageal reflux disease (GERD), Parkinson's disease levodopa-induced dyskinesia (PD-LID), fragile X syndrome (FXS), autism, addiction, and depression. Areas covered: This review begins with an update of the clinical trial efforts with mGlu5 NAMs. Following that update, the review summarizes small molecule mGlu5 NAM patent applications published between 2010 and 2012. These summaries are subdivided into three separate groups: inventions related to improvements in drug properties and/or developability, new chemical entities that contain a disubstituted alkyne, and new chemical entities that do not contain a disubstituted alkyne. Expert opinion: Given the abundant promise found within the mGlu5 NAM field, optimism remains that a drug will emerge from this therapeutic class. Still, the launch of a new drug is far from a certainty. It is encouraging to observe the ever-increasing chemical diversity among mGlu5 NAMs. Finally, in spite of the mature nature of this field, room remains for new advancements. 相似文献
995.
《Expert opinion on therapeutic patents》2013,23(11):1593-1604
Glutamate is the main excitatory neurotransmitter in the mammalian CNS and it exerts its action through ionotropic and metabotropic receptors. Whereas ion channels have been heavily exploited in the recent past, metabotropic glutamate receptor (mGlu) research has been hampered by the lack of potent and selective molecules with ‘drug-like’ structures. A new wave of ligands has recently been disclosed by a number of pharmaceutical companies highlighting the great interest around these potential therapeutic targets. This review endeavours to provide the reader with an updated and detailed panorama of the patent literature of this exciting field, also tackling non-competitive and allosteric modulators. Those skilled in the art know that it is quite difficult to extract structure–activity relationship (SAR) information from a patent or to draw ‘definitive’ conclusions on a compound if biological data are not specifically provided. Accordingly, the main aim of this review will be to provide the reader with the most relevant information available and to report the structures of the newly unveiled chemical entities. Other very interesting compounds recently disclosed in the primary literature will not be exhaustively covered here, but they are surely worth a further check in the available literature databases, a few examples will be mentioned only where a novel therapeutic area is disclosed or if major insights are provided. 相似文献
996.
《Expert opinion on investigational drugs》2013,22(10):1335-1341
Schizophrenia is, at once, a biological disease, a neuropsychological disorder and a dysfunction of social interactions. This presents clinicians with a series of problems with regards to therapy. In the first section of this article, some of the clinical challenges that face those attempting to develop new drugs, are summarised. Several potential pharmacological therapeutic targets that have been, and are continuing to be used, in the development of new antipsychotic drugs, are then considered. This is followed by an outline of the pharmacological and clinical profiles of some of the newer generation antipsychotics, as well as investigational drugs in the pipeline for schizophrenia. Finally, the implications of the introduction of these new drugs for the management of schizophrenia, are discussed. 相似文献
997.
《Pharmaceutical biology》2013,51(12):1328-1336
Aim: Growing evidence indicates that the glutamatergic system, especially the abnormalities of glutamate and N-methyl-D-aspartate (NMDA) receptors contribute to the pathophysiology and possibly the pathogenesis of major depressive disorders. This study is to evaluate the effect of gan mai da zao (GMDZ) decoction on glutamate and NMDA receptor in unpredictable chronic mild stress (UCMS) rats.Materials and methods: Sucrose preference test and open field test were used to estimate the depressive-like behaviors of UCMS rats. Glutamate levels and NMDA receptor subunits (NR1, NR2A and NR2B) in the frontal cortex and hippocampus were determined by HPLC-FLD and by western-blot respectively.Results: 32 days UCMS induced depressive-like behaviors, increased glutamate concentration and decreased NMDA receptor subunits NR2A and NR2B in the frontal cortex and hippocampus of rats. However, NR1 expression remained constant in stressed rats compared with normal. The GMDZ decoction alleviated the depressive-like behavior, decreased glutamate level, and increased expression of NMDA receptor subunit NR2A and NR2B in the frontal cortex and hippocampus of stressed rats.Conclusions: These results suggest that GMDZ treatment reversed chronic unpredictable stress-induced depressive-like behaviors in UCMS rats, possibly via reducing glutamate levels and increasing the NMDA receptor subunits NR2A and NR2B in frontal cortex and hippocampus. 相似文献
998.
Although cholecystokinin (CCK) has long been known to exert anxiogenic effects in both animal anxiety models and humans, the underlying cellular and molecular mechanisms are ill-defined. CCK interacts with CCK-1 and CCK-2 receptors resulting in up-regulation of phospholipase C (PLC) and protein kinase C (PKC). However, the roles of PLC and PKC in CCK-mediated anxiogenic effects have not been determined. We have shown previously that CCK facilitates glutamate release in the hippocampus especially at the synapses formed by the perforant path and dentate gyrus granule cells via activations of PLC and PKC. Here we further demonstrated that CCK enhanced NMDA receptor function in dentate gyrus granule cells via activation of PLC and PKC pathway. At the single-channel level, CCK increased NMDA single-channel open probability and mean open time, reduced the mean close time, and had no effects on the conductance of NMDA channels. Because elevation of glutamatergic functions results in anxiety, we explored the roles of PLC and PKC in CCK-induced anxiogenic actions using the Vogel Conflict Test (VCT). Our results from both pharmacological approach and knockout mice demonstrated that microinjection of CCK into the dentate gyrus concentration-dependently increased anxiety-like behavior via activation of PLC and PKC. Our results provide a novel unidentified signaling mechanism whereby CCK increases anxiety. 相似文献
999.
Ortuño-Sahagún D Rivera-Cervantes MC Gudiño-Cabrera G Junyent F Verdaguer E Auladell C Pallàs M Camins A Beas-Zárate C 《Hippocampus》2012,22(2):128-140
Multiple factors are involved in the glutamate-induced excitotoxicity phenomenon, such as overload of ionotropic and metabotropic receptors, excess Ca(2+) influx, nitric oxide synthase activation, oxidative damage due to increase in free radicals, and release of endogenous polyamine, among others. In order to attempt a more integrated approach to address this issue, we established, by microarray analysis, the hippocampus gene expression profiles under glutamate-induced excitotoxicity conditions. Increased gene expression is mainly related to excitotoxicity (CaMKII, glypican 2, GFAP, NCX3, IL-2, and Gmeb2) or with cell damage response (dynactin and Ecel1). Several genes that augmented their expression are related to glutamatergic system modulation, in particular with NMDA receptor modulation and calcium homeostasis (IL-2, CaMKII, acrosin, Gmeb2, hAChE, Slc83a, and SP1 factor). Conversely, among genes that diminished their expression, we found the Syngap 1, which is downregulated by CaMKII, and the MHC II, which is downregulated by glutamate. Changes observed in gene expression induced by monosodium glutamate (MSG) neonatal treatment in the hippocampus are consistent with the activation of the mechanisms that modulate NMDA receptor function as well as with the implementation of plastic response to cell damage and intracellular calcium homeostasis. Regarding this aspect, we report here that NCX3/Slc8a3, a Na(+)/Ca(2+) membrane exchanger, is highly expressed in astrocytes, both in vitro and in vivo, in response to glutamate-induced excitotoxicity. Hence, the results of this analysis present a broad view of the expression profile elicited by MSG neonatal treatment, and lead us to suggest the possible molecular pathways of action and reaction involved under this experimental model of excitotoxicity. 相似文献
1000.
目的研究神经活性肽urocortinⅡ(UCNⅡ)对大鼠纹状体(STR)神经元自发放电的影响,及对STR中谷氨酸能(glutamate,GLU)神经传递的改变,探讨其在帕金森(PD)发病中的重要作用。方法本实验采用60只SD大鼠,借助多管微电泳方法观察UCNⅡ对大鼠STR神经元自发放电的影响,以及是否存在浓度依赖性,同时微电泳促肾上腺皮质激素调节因子(CRF2)受体阻断剂astressin(AST),确定UCNⅡ对STR神经元放电影响是否通过CRF2受体。另外,在微电泳GLU过程中,微电泳UCNⅡ及AST,观察其对GLU能神经传递的影响。结果微电泳UCNⅡ可使84%(49/58)受试神经元放电频率减慢(P<0.01),其抑制作用存在浓度依赖性。另外,UCNⅡ抑制作用可被AST所拮抗(P<0.01)。在微电泳GLU过程中,给予UCNⅡ可拮抗GLU的兴奋作用,AST可增强GLU的兴奋作用。结论 UCNⅡ通过与CRF2受体结合后能抑制STR神经元,同时影响GLU能神经递质活动在STR生理及病理情况下起调节作用。 相似文献