The NMDA/D1 receptor complex as a new target in drug development

Dopamine and glutamate have been shown to extensively interact in the striatum, nucleus accumbens, hippocampus and prefrontal cortex, to regulate different physiological functions, including locomotor activity, positive reinforcement, attention and working memory. Although dysfunctions of dopamine transmission have long been identified as critical determinants of neurological and neuropsychiatric disorders, such as Parkinson's disease and schizophrenia, there is now increasing evidence that concurrent alterations of dopamine and glutamate function may play a central role in the pathophysiology of these diseases. Thus, defining the characteristics of dopamine-glutamate interactions may be crucial to identify alternative molecular targets for the development of novel pharmacological tools. At the postsynaptic level, interactions between the dopamine D1 and the glutamate NMDA receptors appear to be particularly relevant. Different mechanisms are involved in this interactions: 1) D1R-dependent, second messenger-mediated phosphorylation of NMDAR subunits; 2) coordinated regulation of receptor trafficking at synaptic sites; 3) formation of an heteromeric D1/NMDA receptor complex. In this paper we review the molecular mechanisms, functional implications and pharmacological significance of D1R/NMDAR interaction via direct protein-protein oligomerization.     

The endocannabinoid system in ageing: a new target for drug development

Endocannabinoids are a new class of lipids, which include amides, esters and ethers of long chain polyunsaturated fatty acids. Anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol are the main endogenous agonists of cannabinoid receptors able to mimic several pharmacological effects of Delta(9)-tetrahydrocannabinol, the active principle of Cannabis sativa preparations like hashish and marijuana. AEA is released "on demand" from membrane lipids, and its activity at the receptors is limited by cellular uptake followed by intracellular hydrolysis. Together with AEA and congeners, the proteins which bind, synthesize, transport and hydrolyze AEA form the "endocannabinoid system". Endogenous cannabinoids are present in the central nervous system and in peripheral tissues, suggesting a physiological role as broad spectrum modulators. This review summarizes the main features of the endocannabinoid system, and the latest advances on its involvement in ageing of central and peripheral cells. In addition, the therapeutic potential of recently developed drugs able to modulate the endocannabinoid tone for the treatment of ageing and age-related human pathologies will be reviewed.     

应激与抑郁症发病的相关性及新药研究进展

重度抑郁症是全球范围内最大的公共卫生难题之一,其具有反复性和周期性,可严重影响患者正常的工作能力和社会活动。应激是指外界刺激影响机体内环境稳态而引起的机体非特异性反应,长期的慢性应激通过激活并损伤下丘脑一垂体．肾上腺（HPA）轴及抑制海马神经元冉生诱发抑郁症。本文就应激、HPA轴在抑郁发病机制中的重要作用以及与该机制相关的抗抑郁药的研究进展进行综述。     

The cancer stem cell paradigm: a new understanding of tumor development and treatment

Importance of the field: Cancer is the second leading cause of death in the United States, and therefore remains a central focus of modern medical research. Accumulating evidence supports a ‘cancer stem cell’ (CSC) model – where cancer growth and/or recurrence is driven by a small subset of tumor cells that exhibit properties similar to stem cells. This model may provide a conceptual framework for developing more effective cancer therapies that target cells propelling cancer growth.

Areas covered in this review: We review evidence supporting the CSC model and associated implications for understanding cancer biology and developing novel therapeutic strategies. Current controversies and unanswered questions of the CSC model are also discussed.

What the reader will gain: This review aims to describe how the CSC model is key to developing novel treatments and discusses associated shortcomings and unanswered questions.

Take home message: A fresh look at cancer biology and treatment is needed for many incurable cancers to improve clinical prognosis for patients. The CSC model posits a hierarchy in cancer where only a subset of cells drive malignancy, and if features of this model are correct, has implications for development of novel and hopefully more successful approaches to cancer therapy.     

The role of airway dendritic cell populations in regulation of T-cell responses to inhaled antigens: atopic asthma as a paradigm.

Chronic atopic asthma in adulthood represents the end stage of a disease process that is initiated during the perinatal period, when the naive immune system is first confronted with potentially allergenic airborne antigens. The initial phase involves compartmentalization of immunological memory into either the T-helper (Th)-1 or Th2 cytokine phenotypes, in atopic and nonatopics, respectively, and in a subset of atopics, this results in chronic Th2 cytokine-driven inflammation in the airways. Dendritic cells appear to play a key role in directing the memory generation process, and in subsequently controlling the intensity and duration of the ensuing Th-cell responses responsible for this inflammation.     

The heart of drug discovery and development: rational target selection

Critical to the discovery and development of drugs and vaccines is the rational selection of biochemical, immunologic or molecular targets. To understand the rationale for target selection, we review strengths and weaknesses of the four main approaches: whole animal disease models; molecular targeting; epidemiology/observation studies, and genomics. After classifying diseases into those with a relatively stable pathophysiology (e.g., hypertension and gout) versus those with an unstable pathophysiology (e.g., AIDS and influenza) to aid in understanding target selection, we provide examples of successful and unsuccessful selection of drug and vaccine targets, focusing on the molecular and epidemiological/observational approaches. We discuss the reasons that molecular targeting has led to successful control of many diseases, whereas the epidemiological/observational approach has had a checkered history. We also assess the potential power of the genomic approach, specifically the curative versus controlling/preventive strategies. With combined genetic and molecular approaches and judicious use of whole animal models and properly performed epidemiology/observation studies to select the appropriate targets, the future for controlling, preventing and even curing many diseases is very bright indeed.     

The hERG K+ channel: target and antitarget strategies in drug development.

The human ether-à-go-go related gene (hERG) K+ channel is of great interest for both basic researchers and clinicians because its blockade by drugs can lead to QT prolongation, which is a risk factor for torsades de pointes, a potentially life-threatening arrhythmia. A growing list of agents with "QT liability" have been withdrawn from the market or restricted in their use, whereas others did not even receive regulatory approval for this reason. Thus, hERG K+ channels have become a primary antitarget (i.e. an unwanted target) in drug development because their blockade causes potentially serious side effects. On the other hand, the recent identification and functional characterization of hERG K+ channels not only in the heart, but also in several other tissues (e.g. neurons, smooth muscle and cancer cells) may have far reaching implications for drug development for a possible exploitation of hERG as a target, especially in oncology and cardiology.     

哮喘治疗新靶点——RhoA/Rho激酶及其抑制剂开发

RhoA/Rho激酶参与细胞有丝分裂、黏附、细胞骨架调整、肌细胞收缩及肿瘤细胞浸润等过程.RhoA/Rho激酶信号通路在气道炎症细胞迁移、趋化和浸润过程中起关键性的调控作用,是哮喘治疗药物的潜在靶点.本文综述RhoA/Rho激酶信号通路在哮喘气道炎症、气道重塑和气道高反应性(AHR)的作用及其机制以及Rho激酶抑制剂的开发近况.     

Shifting the main purposes of drug control: from suppression to regulation of use: Reduction of risks as the new focus for drug policy

I believe that the original aims of (almost full) prohibition of substance use, as it is applied according to the NY Single Convention of 1961, are unattainable. Instead, I want to present some arguments and ways of looking at drug use that support a far reaching revision of the current aims of drug control. Drug policy goals should shift, from suppression of use to regulation of use.¹ In this article I will present drug use data collected in Amsterdam that in my view support such a shift. Ten years of drug use data in the population of Amsterdam show a remarkable level of control and stability in drug use patterns in a policy environment that allows relatively easy access to drugs. Internal controls on drug use can be expected to play a much larger part in structuring these patterns than classic drug policy theory allows for.     

维生素D水平与冠心病发病相关性初步研究

目的初步探讨血清维生素D(VitD)水平与冠心病之间的关系。方法对177例温州地区冠状动脉造影者测定静息血压、25(OH)D水平、甘油三酯(TG)、总胆固醇(TC)、低密度脂蛋白(LDL)、高密度脂蛋白(HDL)及血糖(FPG)及超敏C反应蛋白(hs-CRP)水平,并根据造影结果分为冠心病组和对照组,冠心病组再分为2个亚组:急性冠状动脉综合征组(ACS组)和慢性缺血综合征组(CIS组)。结果冠心病组收缩压、FPG、hsCRP、25(OH)D水平均明显高于对照组(P<0.05或P<0.01),但ACS组仅血清hs-CRP明显高于CIS组(P<0.01),余差异均无统计学意义(P>0.05)。结论低血清维生素D水平与冠心病发病相关,可能通过影响收缩压与血糖成为冠心病的潜在危险因子。     

The pivotal role of drug metabolism and pharmacokinetics in the discovery and development of new medicines

An appropriate drug metabolism and pharmacokinetic (DMPK) profile remains a major hurdle to reducing risk and improving productivity in pharmaceutical R&D, accounting for approximately 40% of all drug failures. For orally administered drugs, failure is often attributable to low intestinal absorption and/or high clearance, causing poor and variable bioavailability. Additional reasons for failure include drug-drug interactions and the presence of active metabolites. With a poor pharmacokinetic profile, it can be difficult to achieve the dose profile required for therapeutic efficacy. The main role that DMPK plays in drug discovery is therefore the prediction of drug metabolism and pharmacokinetics in humans. Successful prediction can be expected to reduce the rate of attrition during drug discovery and development. This has led to the recognition that DMPK is an essential component of the drug discovery process. Both this and the need to screen ever greater numbers of compounds have led to major changes in both technology and the process of drug discovery.     

胶质细胞活化在病理性疼痛发展过程中的意义：对药物研发的启示

近年来有关胶质细胞在病理性疼痛发生和发展过程中的作用越来越受到了重视。目前认为小胶质细胞和星形胶质细胞在外周神经或组织损伤后被激活并产生各种炎性介质,成为病理性疼痛发生发展过程中重要的致痛因素,针对胶质细胞活化及其后产生的炎性介质有可能研发出新型抗病理性疼痛药物。本文就此方面的研究进展做一综述,试图为靶向胶质细胞研发新型抗病理性疼痛药物提供新的线索。     

The MEP pathway: a new target for the development of herbicides, antibiotics and antimalarial drugs

Isoprenoids, a diverse group of compounds derived from the five-carbon building units isopentenyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP), are essential for survival in all organisms. Animals synthesize their isoprenoids from mevalonic acid (MVA), whereas most pathogenic bacteria and the malaria parasites utilize a completely different pathway for IPP and DMAPP synthesis, the methylerythritol phosphate (MEP) pathway. Plants use both pathways for the synthesis of isoprenoid precursors. The recent elucidation of the MEP pathway has opened the possibility to develop new strategies against microbial pathogens. Novel immunotherapeutic agents can be developed based on the MEP pathway intermediates known to activate the proliferation of human V-delta-9 V-gamma-2 T-cells after infection by many pathogenic bacteria and protozoa. Moreover, the design of specific inhibitors of MEP pathway enzymes (which are highly conserved but show no homology to mammalian proteins) should result in herbicides and drugs with broad-spectrum antimicrobial activity without mechanism-based toxicity to humans. A good example is the cure of bacterial infections and malaria with fosmidomycin, a highly stable inhibitor of the MEP pathway. The use of plants as test systems has led to the identification of additional inhibitors such as ketoclomazone. Biochemical, genetic and crystallographic approaches with the MEP pathway enzymes are now starting to characterize the inhibition kinetics and identify which residues play a structural or catalytic role. Current efforts should eventually contribute to an effective drug designed to fight against microbial pathogens that show resistance to currently available agents.     

The role of in vivo molecular imaging with PET and SPECT in the elucidation of psychiatric drug action and new drug development

This paper reviews the contribution of human PET and SPECT neuroreceptor occupancy studies to the understanding of drug action in psychiatric illness, and how they can aid the development of new drugs. All effective antipsychotics show significant D₂ receptor occupancy. However, at least for atypical antipsychotics, there is no clear relationship between occupancy and clinical response. The mechanisms underlying antipsychotic efficacy, and the minimal effective D₂ occupancy, remain to be elucidated, particularly for drugs with modest or transient occupancy. The low liability of some atypical antipsychotics for extrapyramidal side effects does not appear to be explained by their 5-HT_2A antagonism, and the muscarinic receptor occupancy of some drugs may be partly explanatory. Previous reports of apparent ‘limbic selectivity’ of atypical antipsychotics may be in error, and may be due to technical differences in radiotracers. For SSRIs, high occupancies at the serotonin transporter (SERT) are achieved at therapeutic doses, although the minimum SERT occupancy required for therapeutic response remains undefined. Previous attempts to augment the antidepressant effect of SSRIs by pindolol have generally used daily doses which result in inadequate 5-HT_1A receptor occupancy. For benzodiazepines, clinical doses would appear to leave a wide margin of unoccupied receptors. For methylphenidate and cocaine, typical doses occupy more than 50% of dopamine transporters, and their profiles are extremely similar. In therapeutic drug development, these techniques may be used to assess receptor occupancy profiles, likely drug dosages and dosing intervals which cannot be reliably assessed in humans by other methods.     

The new drug approvals of 1987, 1988, and 1989: trends in drug development

The new drug approvals of 1987, 1988, and 1989 were analyzed to determine whether there are any emerging trends in the US drug development and review processes. Sixty-four new drugs were approved by the FDA during this period, of which 55 met the Center for the Study of Drug Development's definition of a new chemical entity (NEC). For the 55 NCEs, the mean length of the investigational new drug application (IND) phase (IND filing to NDA submission) was 5.2 years, the new drug application (NDA) phase (NDA submission to approval) was 2.9 years, and the total phase (IND filing to NDA approval) was 8.1 years. Nine of the 55 NCEs were classified by the FDA as 1A (important therapeutic gain), 15 were classified as 1B (modest gain), 29 were classified as 1C (little or no gain), and 2 were classified as 1AA (drugs to treat AIDS and AIDS-related conditions); 10 drugs were granted orphan status. The mean NDA phase for 1A drugs was 2.4 years; 1B drugs, 2.9 years; 1C drugs, 3.1 years; 1AA drugs, 1.4 years; and orphan drugs, 2.5 years. Forty-four of the 55 NCEs (80%) were available in foreign markets before US approval was given, with a mean of 6.5 years of prior marketing. These data are consistent with figures for previous years and suggest little change in the rate of new drug development and review in the United States.