Faculty of Pharmaceutical Sciences University of Copenhagen

List of projects for exchange students from partner universities

Academic year 2009-2010

Please read this information before you read the list of projects below

As an exchange student at the Faculty of Pharmaceutical Sciences (PHARMA), University of Copenhagen you may work as a project students on research projects provided that an academic staff member at PHARMA accepts to supervise you during your stay.

You will be registered on an “individualised study unit” and will receive a maximum of 30 ECTS credit points for your project work. There will be an examination with the academic supervisor at the end of the “Individualised study unit” where a written report, poster, paper, oral examination or similar, in which you summarise the goals, results and conclusions from the project.

Another option is to work on an MSc thesis at PHARMA. If you register as an MSc thesis student you will have to write and defend your MSc thesis at PHARMA and will receive 30-60 ECTS credit points. You will not receive a full MSc degree from PHARMA.

The application deadlines for exchange students that wish to apply for an “Individualised study unit” or an MSc thesis at PHARMA are May 1, for studies in the autumn semester and October 1, for studies in the spring semester.

Please read more about application on http://www.farma.ku.dk/index.php/Admission-exchange/4669/0/ You are requested to provide the following information in the space “Description of Studies” in the application form:

• requested study period at PHARMA (start and end of stay) • a list of project(s) that you are interested in (please prioritise the projects) • a thorough description of your academic prerequisites and interest in each of the projects • please indicate if you have already made an agreement with an academic supervisor at

PHARMA

After application the academic faculty members will evaluate your academic qualifications and will decide if you will be admitted to the project.

PHARMA offers many research projects and subjects in addition to the ones on the list below.

If you are not interested in the project ideas below you might want to contact a faculty member or a research group to ask if you can undertake a project with them. Please send them a proposal including your CV, transcript of records and a description of the subject/project that interests you and a thorough description of your previous qualifications within the subject.

To find information about research areas at the Faculty of Pharmaceutical Sciences please take a look at the Danish version of the faculty home page www.farma.ku.dk under “institutter” (i.e. departments). Each of the three department homepages contains a description of research areas including staff in the research groups.

List of project ideas

Projects at the Department of Pharmaceutics and Analytical Chemistry

A1. Process analytical technology, PAT (JTR) Process analytical technology (PAT) is a new way to look into pharmaceutical production. The main aim is to achieve relevant information during processing and by this means increase the level of safety. Current projects in this area cover the unit operations related to solid dosage forms, specifically the implementation of non-invasive spectroscopic methods for process monitoring and control purposes. Students have a possibility for industrial and academic projects in both Denmark and outside of Denmark (UK, USA, Sweden, and Finland). Max. number of students: 2 For further information, please contact Jukka Rantanen at The Department of Pharmaceutics and Analytical Chemistry: jtr@farma.ku.dk

A2. Dry powder inhalation, DPI, at AstraZeneca, Lund Pulmonary drug delivery technologies are one of the key formulation possibilities for challenging new molecules. However, we should be able to design particles with controlled properties. This project is aiming to develop new insights into characterization of critical particulate properties in relation to dry powder inhalation products. Main focus is on relating segregation tendency to the surface characteristics of powder particles. Exsperimental work will be performed at AstraZeneca (Lund). For further information, please contact Jukka Rantanen at The Department of Pharmaceutics and Analytical Chemistry: jtr@farma.ku.dk

A3. Drug – biomacromolcule interactions. Determination of equilibrium constants and association- and dissociation rate constants. The interaction of a drug substance with a receptor or a protein is usually characterized by a binding or equilibrium constant (K). The equilibrium constant is given by the ratio between the association and the dissociation rate constants (ka/kd). The magnitudes of the rate constants may be of importance to the fate of drug substances in the body. For instance, the dissociation rate constant of a drug – albumin complex may be a determining factor for liver uptake and metabolism of a strongly bound

drug. The aim of the project is to develop and validate capillary electrophoresis (CE) and surface plasmon resonance (SPR) methods for the determination of equilibrium and rate constants. Max students: 1-2 For further information, please contact Jesper Østergaard or Henrik Jensen at The Department of Pharmaceutics and Analytical Chemistry: joe@farma.ku.dk or hj@farma.ku.dk

A4. Pharmaceutical profiling of drug substances using capillary electrophoresis and electrochemical techniques The chemical structure of a drug substance determines its degree of interaction with pharmaceutical excipients, e.g. cyclodextrins, surfactants and polymers, propensity for ion pair formation, self association, and distribution in two-phase systems. The objective of the project is to develop new micro techniques based on electrochemistry and capillary electrophoresis for the investigation of distribution and complexation phenomena. The methodologies are characterized by being fast and requiring small amounts of sample only. Hence, they may be used in drug discovery/ early drug development potentially offering a more thorough physical chemical characterization at an earlier time point and a better starting point for subsequent drug development. Max students: 1-2 For further information, please contact Jesper Østergaard or Henrik Jensen at The Department of Pharmaceutics and Analytical Chemistry: joe@farma.ku.dk or hj@farma.ku.dk

A5. Adsorption of protein drug compounds to oil-water interfaces An increasing number of drug compounds under development are based on proteins and other biological macromolecules. This type of drug compounds requires different strategies with respect to development, production and analysis as compared to more traditional drug compounds based on smaller molecules. For example, proteins may change their structure irreversible upon adsorption to interfaces (such as those between water and oil) and thereby loose the pharmacological effect. The purpose of this project is to investigate the adsorption of proteins and other macromolecules to oil-water interfaces using a surface sensitive electrochemical method. Adsorption to the oil-water interface can be compared to adsorption onto modified gold surfaces studied by SPR (Surface Plasmon Resonance) techniques. The adsorption measurements will be supported by studies on protein interactions in aqueous solution in order to investigate how potential excipients may influence the adsorption. Max students: 1-2 For further information, please contact Jesper Østergaard or Henrik Jensen at The Department of Pharmaceutics and Analytical Chemistry: joe@farma.ku.dk or hj@farma.ku.dk

A6. Development of Drug Sensors for Monitoring Drug Compounds Throughout the development phase as well as on later stages there is a demand for analytical methods facilitating the measurement of drug compounds in different matrices such as blood, plasma, skin or urine. Traditional approaches typically involve separate sampling, sample preparation separation and detection steps. It will be advantageous if the analysis can be performed on-site and not be dependant on advanced laboratory facilities. The objective of the present project is thus to design sensitive and specific drug sensors. By means of such sensors it will ultimately be possible to monitor individual drugs, their metabolism and disposition and thereby secure proper dosing of the drug compound. In this way unwanted side effects can be avoided. The sensors will

mainly be based on electrochemical principles, but techniques based on SPR (Surface Plasmon Resonance) will be included where relevant. Max students: 1-2 For further information, please contact Henrik Jensen at The Department of Pharmaceutics and Analytical Chemistry: hj@farma.ku.dk

A7. Liposome – drug interactions Liposomes consist of a lipid double layer. The structural characteristics resemble to a large degree those of biological membranes and, consequently, liposomes constitute an attractive model of such membranes. Furthermore, drug delivery systems based on liposome technology has been investigated and utilized for a number of years. The objective of the project is to develop capillary electrophoresis (CE) and surface plasmon resonance (SPR) based micro-analytical methods for investigation of drug – liposome interactions. The methods will be used for characterization of drug – liposome distribution coefficients, membrane adsorption, and membrane permeability studies as well as for the characterization of liposome drug delivery vehicles, e.g. stability, drug incorporation efficiency and membrane leakage. Max students: 1-2 For further information, please contact Jesper Østergaard at The Department of Pharmaceutics and Analytical Chemistry: joe@farma.ku.dk

A8. Permeability assessment of poorly water-soluble compounds under solubilizing conditions: getting the correct permeability by correction for the micellar bound fraction Bile salts, as a natural surfactant in the gastrointestinal tract, play an important role in the absorption processes for compounds with a low aqueous solubility; hence they are applied in a number of in vitro assays used for prediction of oral absorption in the drug discovery phase. One of the absorption screening models is based on the Caco-2 cell line, in which bile salts are added to solubilize the compounds. This, however, may lead to an inaccurate estimate of permeability as only the free drug is available for permeation. The objective of the project is to develop capillary electrophoresis (CE) and/or membrane (dialysis) based methods for the determination of the free fraction of drug in bile salt media in order to obtain improved permeability data for compounds with poor aqueous solubility. In collaboration with René Holm (H. Lundbeck A/S) Max students: 1-2 For further information, please contact Jesper Østergaard at The Department of Pharmaceutics and Analytical Chemistry: joe@farma.ku.dk

A9. Design of in situ forming oil suspensions of peptide-based drug candidate Intra-articular administration of chondrocyte stimulating peptides has potential curative effects in the area of osteoarthritis. In situ oil suspension-forming depots can be achieved by design of biocompatible oil-cosolvent solutions of peptide derivatives that in contact with the aqueous synovial fluid leads to a phase separation resulting in drug precipitation in the oil phase from which the active agent is slowly release into the joint cavity. The goal of this project include i) physicochemical characterization of model peptides and ii) investigation of in vitro release and transport processes of oil suspension-forming delivery systems Max students: 1-2 For further information, please contact Jesper Østergaard at The Department of Pharmaceutics and Analytical Chemistry: joe@farma.ku.dk

A10. Design of intra - articularly injectable oil depots providing local prolonged balanced analgesia Intra-articular injection of oil depot formulations containing two analgesic drug compounds acting by different mechanisms (multimodal analgesia) might contribute to improved effectiveness of postoperative pain control after arthroscopic surgery. In order to create a scientific template for rational design of novel prolonged release drug delivery systems feasible for intra-articular administration the purpose of the project is to i) identify and possibly quantify physicochemical and enzymatic events in vitro which are likely to be operating for drugs/prodrugs injected into the synovial space in the form of oil solutions and to ii) investigate the time dependence of these interrelated events each of which influencing drug residence time in the joint. Max students: 1-2 For further information, please contact Jesper Østergaard at The Department of Pharmaceutics and Analytical Chemistry: joe@farma.ku.dk

A11. Stabilisation of spray dried proteins Spray drying of protein solutions may cause chemical and physical degradation of the proteins and often stabilising excipients are required to obtain a stable product. The stabilising effect of excipients is largely unknown but some excipients affect both the physical characteristics of the powder and the in vivo effect of the protein. In this study the stabilising effect of different excipients will be investigated in addition to their effect on the powder characteristics of the solid formulation. The available techniques include, but are not limited to, spray drying, high performance liquid chromatography (HPLC), Fourier transform infrared spectroscopy (FTIR), circular dichroism (CD), solid state differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). For further information, please contact Marco van de Weert at The Department of Pharmaceutics and Analytical Chemistry: mvwd@farma.ku.dk

A12. Effect of protein modifications on solid formulations Spray drying is taking over the status of freeze drying as the preferred drying method for proteins. Presently most research has been done on natural occurring proteins, but focus is changing to new analogous and modified proteins. The effect of for example amino acid substitutions and especially acylation or pegylation on the solid formulation is not well investigated. This study will focus on the relationship between protein modifications, protein integrity and solid formulation characteristics. The available techniques include but are not limited to spray drying, high performance liquid chromatography (HPLC), Fourier transform infrared spectroscopy (FTIR), circular dichroism (CD), solid state differential scanning calorimetry (DSC) and scanning electron microscopy (SEM). For further information, please contact Marco van de Weert at The Department of Pharmaceutics and Analytical Chemistry: mvwd@farma.ku.dk

A13. Protein fibrillation and reversal of protein fibrillation All proteins have the intrinsic property to form large, fibril-like aggregates, known as amyloid fibrils. These fibrils are common in diseases like Alzheimer’s, Parkinson’s and Creutzfeldt-Jakob Disease (CJD), but can also be formed by protein drugs. There is, at present, no practical method to reverse protein fibrillation, but some compounds have been shown to reverse the fibrillation process.This project is aimed at investigating the action of these fibrillation-reversers, and at evaluating their ability as a potential drug or as stabilising additive. The work will mainly comprise of determining (de-)fibrillation kinetics using a high-throughput assay, as well as the use of

advanced analytical tools to investigate how the various compounds are able to reverse the fibrillation process. Measuring the cellular toxicity of the compounds, as well as the various protein aggregate intermediates of the (de-)fibrillation process may also be part of the project. For further information, please contact Marco van de Weert at The Department of Pharmaceutics and Analytical Chemistry: mvwd@farma.ku.dk

A14. Lyophilization of nanoparticulate systems Lyophilization, or freeze-drying, is a common process to obtain long-term stability of so-called nanoparticulate carriers, nanosized structures in which a drug is incorporated. These carrier systems are not very robust, and a quite common process like freeze-drying then becomes a real art. In this project you will investigate the influence of several parameters during freeze-drying on the characteristics of selected nanoparticulate systems, e.g., liposomes. For further information, please contact Marco van de Weert at The Department of Pharmaceutics and Analytical Chemistry: mvwd@farma.ku.dk

A15. Lyophilization of protein formulations Lyophilization, or freeze-drying, is a common process to obtain long-term stability of protein drugs. However, proper lyophilization is an art, and requires a thorough understanding of the processes in the freeze-dryer. Various novel protein stabilizers are being developped, and their use in a commercial product often requires that they can be incorporated in the lyophilized protein formulation. In this project you will test the effect of using certain novel stabilizers in lyophilized protein formulations. For further information, please contact Marco van de Weert at The Department of Pharmaceutics and Analytical Chemistry: mvwd@farma.ku.dk

A16. Spray-dried nanoparticulate delivery systems for pulmonary delivery of small nucleic acids The objective of this project is to prepare and characterize siRNA-containing spray-dried powders for in vivo assessment of small nucleic acid inhalation in mice. To our knowledge, no in vivo application of small nucleic acid spray-dried powders have been reported so far. Non-viral gene delivery to the lung has a long history of development, and it is now poised to represent a significant addition to the medical arsenal. To date, most experimental and clinical studies employ the nebulizer as pulmonary gene delivery device, even though the dry powder system has distinguished advantages compared with nebulisation including increased physicochemical stability of biomacromolecules, reduced drug loss and more efficient delivery to the lung. Non-viral nanoparticles based on lipids and polymers will be used as carriers. Disaccharides and amino acids are employed as spray drying process protectants. A Büchi B-290 Mini Spray Drier with an improved cyclone is used in dry powder design, which offers a possibility to handle batch sizes of less than 100 mg. The HeLa and Calu-3 cell lines will be used to evaluate transfection efficiency and to screen optimized formulations. The spray-dried powders will be used for future in vivo knock-down trials performed in mice after intratracheal administration of small nucleic acid spray-dried powders by a surgery method (animal studies will, however, not be a part of this project). For further information, please contact Camilla Foged or Dongmei Cun at The Department of Pharmaceutics and Analytical Chemistry: cfo@farma.ku.dk or dcun@farma.ku.dk

A17. Poly (Lactide-Coglycolide) micro particles as adjuvant in vaccine for pigs This project focuses on the usefulness of Poly (lactide-coglycolide) micro particles (PLG-micro particles) as adjuvant in a vaccine against Mycoplasma hyosynoviae - a bacterium that causes joint

disease in pigs. PLG is a biodegradable polymer, which can be used as adjuvant when vaccine antigens are incorporated in PLG micro particles, ’microspheres’. The adjuvant effect of these consists in that when the antigen-loaded PLG microspheres are injected e.g. intramuscularly, a continuous release of antigen takes place. In this way you achieve a high local concentration of vaccine antigen during a prolonged period of time. The entry of the vaccine antigens into the lymph nodes, as well as their interaction with antigen presenting cells are promoted by incorporation into PLG microspheres. It has been shown that this type of adjuvant is successful in both inducing a cell mediated immune response as well as a humoral immune response. Induction of a cell mediated immune response at immunization is desirable in the prophylaxis against several infectious diseases, both in veterinary and human medicine. Furthermore, encapsulation of vaccine into PLGA microspheres is a promising approach for single-dose vaccines. The master project includes development and characterization of the adjuvant i.e. a thorough optimization of particle size and of surface structure of microspheres before used as an adjuvant. This part will take place at KU-FARMA. The ability of the resulting adjuvant to induce both cell mediated and humoral immune response in pigs will be tested at the Danish Institute for Food and Veterinary Research (DFVF) in combination with a Mycoplasma hyosynoviae vaccine antigen. The project will be carried out in close relation to an existing DFVF project;”Vaccine development with the aim of preventing lameness in swine caused by Mycoplasma hyosynoviae”. In cooperation with Klara Tølbøll Lauritsen (DFVF) For further information, please contact Camilla Foged at The Department of Pharmaceutics and Analytical Chemistry: cfo@farma.ku.dk

A18. Phospholipase A2 sensitive liposomes for siRNA delivery LiPlasome Pharma A/S LiPlasome Pharma A/S is a biotech company with focus on development of a new drug delivery system concerning treatment of cancer. LiPlasome Pharma’s drug delivery technology is based on design of liposomes with a special designed lipid composition, which makes the liposome degradable by secretory phospholipase A2 (sPLA2). The liposomes are designed to be steady in the blood circulation, which means that the encapsulated drug will not be released until is comes near the tumor cells, where a high expression of sPLA2 is present. In that way the local concentration of the active drug and the effect of this are increased. Apart from that the systemic exposure is reduced and with that the usual dose limited adverse events.

A new focus area is the liposomal delivery of siRNA. The present project may include preparation, selection and characterization of PLA2-sensitive liposome compositions for the encapsulation of siRNA molecules. If the time is sufficient, the transfection of the siRNA containing liposomes will be tested as well. For further information, please contact Camilla Foged or Hanne Mørck Nielsen or Lene Jørgensen at The Department of Pharmaceutics and Analytical Chemistry: cfo@farma.ku.dk or hmn@farma.ku.dk or lej@farma.ku.dk

A19. Functional delivery of small interfering RNA – by use of polymers such as dendrimers Small interfering RNAs (siRNA) are recognized as promising drug candidates for gene silencing, as they posses great therapeutic potential for treatment of multiple, serious and often chronic diseases such as cancer, infectious diseases and inflammatory diseases like rheumatoid arthritis. The 21 nucleotide double-stranded RNA molecules initiates specific degradation of target mRNA, preventing protein expression and thereby potentially disease progression. However, due to the instability of siRNA in vivo, the large molecular weight and the negative charge of the siRNA

duplexes, the effective cellular uptake and intracellular delivery represents the major challenges for the therapeutic use.

The overall goal of this project is to design polymer based non-viral delivery systems for siRNA, including characterization and functional effect in cellular systems. The aim is to enhance siRNA stability, cellular uptake, efficiency and specificity in mammalian model systems. Potential master projects can embrace parts of the following: Design and preparation of polymer-based delivery systems (i.e. dendrimers or different linear or branched polymers), characteristics and stability of delivery systems and/or evaluation of the systems in cell cultures, including efficiency, uptake mechanism and toxicity. A PhD student will be co-supervisor. For further information, please contact Camilla Foged or Hanne Mørck Nielsen at The Department of Pharmaceutics and Analytical Chemistry: cfo@farma.ku.dk or hmn@farma.ku.dk

A20. Chitosan-modified or CPP-modified PLGA nanoparticles for efficient delivery of siRNA siRNA has been encapsulated in PLGA based particles with a relative high encapsulation efficiency, however, when testing the nanoparticles in cell culture systems, the biological effect is not as high as expected. Therefore, in these projects, we aim at modifying the nanoparticles by: (1) surface coating with another type of polymer (chitosan) or (2) conjugation of a CPP (cell penetrating peptide) to the surface of the nanoparticle in a controlled manner by solid-phase peptide synthesis. The general properties of the drug delivery system and its ability to transport bioactive compounds into cells are investigated. Coating will increase the surface charge of the particles from negative to slightly positive, which might increase the association to living cells. The particles should be prepared, characterized and tested in in vitro cell culture systems. Partly collaboration with researcher at DTU. For further information, please contact Hanne Mørck Nielsen or Dongmei Cun at The Department of Pharmaceutics and Analytical Chemistry: hmn@farma.ku.dk or dcun@farma.ku.dk

A21. Characterisation of the interaction of selected selenium compounds with cell membrane transporters Various selenium compounds have been shown to be cancer protective agents, but the efficacy of the different compounds is still a matter of discussion. How selenium is absorbed across the intestinal membrane is however not investigated. The goal of the present study is to investigate the absorption mechanisms and kinetics of selected selenium compounds in an in vitro intestinal model. The strategy is to use cell cultures such as Caco-2 as a model for the intestinal membrane. Relevant biological media will be used in investigating the role of absorptive/exorptive membrane transporters by using competition assays. For further information, please contact Bente Gammelgaard or Bente Steffansen at The Department of Pharmaceutics and Analytical Chemistry: bg@farma.ku.dk or bds@farma.ku.dk

A22. Efflux transporters in drug delivery. A number of anticancer drugs such as doxorubicin, etoposide and vinblastine are substrates for cellular efflux mechanisms mediated by ATP-dependent transporters such as p-glycoprotein and MRP’s. The expression of these transporters limits the availability of certain compound in the brain,

and also the absorption of some compounds from the gastro-intestinal tract. In in vitro systems the interpretation of flux data for substrates for efflux mechanisms is difficult. The project aims at investigating the relative importance of various efflux transporters in Caco-2 cells for selected substrates, and the implications for in vivo drug absorption and distritution. Max. students: 2 For further information, please contact Birger Brodin or Carsten Uhd Nielsen at The Department of Pharmaceutics and Analytical Chemistry: bbr@farma.ku.dk or cun@farma.ku.dk

A23. Drug delivery via proton coupled amino acid transporters Recently proton-coupled amino acid transporting proteins have been identified in the small intestine. The transporters (hPAT1-4) transport pharmacologically active compounds such as GABA and D-cycloserine. hPAT1 thus seems to be a possible target for increasing the intestinal absorption of analogues of various neuroactive amino acids. Small hydrophilic amino acid mimetics do not normally cross the intestinal barrier unless actively transported by a transport protein. The structural requirements for targeting amino acid analogs to hPAT1 is however largely unknown. The project therefore aims at elucidating structural determinants which are important for transport via hPAT1. Max. students: 2 For further information, please contact Carsten Uhd Nielsen at The Department of Pharmaceutics and Analytical Chemistry: cun@farma.ku.dk

A24. Cell-based methods for investigating amino acid transport. This project combine basic pharmaceutical research with basic molecular biology research with the aim of generating a cell-based in vitro model for measuring transport properties of amino acid mimetic drugs via hPAT1. Transfections, assay development and basic research are key words for this project, which is indented for the ambitious student(s) with an interest and a background in basic research. The transport should be detected using flourescense measurement using available probes. The model will be highly valuable for this groups future research. Max. students: 2 For further information, please contact Carsten Uhd Nielsen at The Department of Pharmaceutics and Analytical Chemistry: cun@farma.ku.dk

A25. Functional analysis of genetic variants of the human proton-coupled peptide transporters hPepT1/hPepT2 Peptide transporters are important for absorption and re-absorption of β-lactam antibiotics and prodrugs. In the human genome several single nucleotide polymorphism (SNP) and alternatively spliced genetic variants exists. We have a number of genetic variants of hPepT1 and hPepT2. For hPepT2 the major haplotype still needs characterization in terms of proton coupling, which may have functional implications for the approximately 50 % of the population, which has this variants. The project aims at characterizing the impact of SNP’s on the proton dependency from both a therapeutic and protein structural point of view. Max. students: 2 For further information, please contact Carsten Uhd Nielsen at The Department of Pharmaceutics and Analytical Chemistry: cun@farma.ku.dk

Projects at the Department of Pharmacology and Pharmacotherapy

B1. Identification of genes important for development of chronic inflammatory diseases Chronic inflammatory diseases, like Multiple Sclerosis (MS) and Rheumatoid Arthritis (RA), are caused by both genetic and environmental factors in a complex interplay. In order to elucidate the underlying factors, the work is focused on the definition of genes that predispose to disease development. In studies of mouse models for MS and RA, a number of important genetic regions have been defined. The aim of the project is to identify candidate genes within these regions and to investigate the role for these genes in disease development. Important candidate genes will, subsequently, be considered as potential drug targets. Techniques used involve: molecular biology (genotyping with PCR, cloning and DNA sequencing, gene expression analyses with real-time PCR); cell work (flow-cytometry, cell-culturing, ELISA); bioinformatics; animal work (mouse). For further information, please contact Åsa Andersson (aaa@farma.ku.dk), Department of Pharmacology and Pharmacotherapy B2. Cardiovascular and smooth muscle pharmacology My major research area is the regulation of vascular tone in health (incl. age-related studies) and disease (diabetic rats and rats with congestive heart failure). We have characterized the receptor subtypes and the signaling pathways for the naturally occurring neuropeptide Calcitonin Gene-Related Peptide (CGRP) in both rat coronary arteries (large and small) and human subcutaneous arteries (large and small). These studies clearly demonstrate a larger CGRP receptor density in small resistance coronary arteries (internal lumen diameter less than 200 micrometer) compared to larger arteries (internal lumen diameter greater than 300 micrometer), indicating that receptor distribution, calcium handling, ion channels and second messengers may be finely adjusted within the circulatory system, probably reflecting the physiological demands on the vascular segments. At the present time, studies are being conducted to characterize the changes in vascular tone and vascular responsiveness in animals developing type II diabetes, ischemic heart disease, and also in hypertensive animals. These studies increase our knowledge of complex regulation of arterial tone and cardiovascular system under different pathological conditions, which will improve diagnosis and treatment of patients either suffering from ischemic cardiovascular diseases or are prone to develop ischemic cardiovascular diseases. A couple of examples of the research projects in my laboratory are listed below:

1- The vascular function and biomarker display in animals developing diet-induced pre-diabetes.

2- The effect of calcitonin gene-related peptide family and capsaicin in isolated vas deferens 3- Molecular and pharmacological characterization of KATP and BKCa-channels in porcine

intracranial arteries. 4- Function of KCNQ - and KCa-channels in the rat urinary bladder. 5- Ca2+ channel antagonistic effect of Eremophilanlactones from Petasites hybridus

(Butterbur): effect on isolated vessels.

6- The effect of organ culture on the vasomotor responses of isolated rat coronary arteries to the contractile agents such as endothelin-1, Sarafotoxin 6c (S6C), Serotonin, Angiotensin II, Noradrenaline and thromboxane A2.

7- The effect of cerebral ischemia (ligation of MCA) and heart ischemia (ligation of LAD) on the vasomotor responses of isolated rat middle cerebral arteries (rMCA: both distal and proximal segments) and coronary arteries (both intramural and septal segments) to various contractile agents.

Methods currently used in my laboratory:

1- Wire Myograph and pressure Myograph. 2- Langendorff heart perfusion system. 3- Measurement of the intracellular calcium concentration in isolated vessels by fluorescence

microscopy (using FURA-2 technique). 4- RT-PCR, Western blotting, ELISA and Immunohistochemistry.

For further information please contact: Majid Sheykhzade, Associate professor, PhD Department of Pharmacology and Pharmacotherapy, Faculty of Pharmaceutical Sciences Phone: (+45) 35336546, Fax: (+45) 3533 6020, E-mail: mash@farma.ku.dk

B3. Ionotropic Glutamate Receptors My research is focused on the study of the AMPA/kainate ionotropic glutamate receptors (iGluRs) and we are employing several different approaches to examine the functional and physiological role of iGluRs. Binding of (S)-glutamate to iGluRs is a key step in rapid excitatory synaptic transmission among nerve cells within the mammalian central nervous system (CNS). iGluRs are important in the development and function of the CNS and are implicated in learning and memory. Furthermore, iGluRs also seem to be associated with certain neurological and psychiatric diseases (e.g. epilepsy, Alzheimer’s, depression) and are therefore considered as potential drug targets. Recombinant receptors are pharmacologically characterized by expression in X. lævis oocytes using TEVC electrophysiology as well as by radioligand binding assays. These pharmacological and functional studies on iGluRs are complemented by biostructural analyses, within FARMA’s GluTarget project (www.glutarget.ku.dk), using X-ray crystallographic investigations of the binding of ligands to receptor binding site(s). Selected compounds from in vitro studies are screened for activity in various behavioural models in vivo. Duration: Minimum 6 months. For further information please contact: Dr. Darryl S. Pickering, assoc. prof. Dept. of Pharmacology & Pharmacotherapy Faculty of Pharmaceutical Sciences University of Copenhagen http://www.farma.ku.dk/index.php/Ionotropic-Glutamate-Receptors/2919/0/

B4. Pharmaceutical Policy – Current trends in Europe This project will look at current and future trends in pharmaceutical policy on an international and national level. The work of the World Bank, UNICEF, The World Health Organization and the EU with regard to pharmaceutical policy will be examined. The project will address two or more of the following questions: What are the major issues? Do these organizations agree on these issues? What is the focus of each of these organizations? Thereafter case studies will be made of one or two EU countries. What are the major policy issues in these countries? How do they comply or differ from those of international organizations? Duration: Minimum 6 months. Prerequisites: Working knowledge (spoken and written) of English, a basic knowledge of methods and theories used in social pharmacy. Suggested elective course: S-369 (Course in International Health Care) (held annually in the fall semester). For further information, please contact Janine Morgall Traulsen, Department of Pharmacology and Pharmacotherapy, Section for Social Pharmacy: jam@farma.ku.dk

B5. Pharmaceutical Policy – current trends in the Nordic countries This will be a Nordic comparative project which looks at and compares current trends in pharmaceutical policy in two (or more) of the following countries: Norway, Sweden, Iceland, Finland, and Denmark. All Nordic countries are currently in the process of drafting up new legislation for the pharmacy sector….a situation which makes for a very interesting and dynamic project. This project will be linked to an on-going project which compares policy trends in Iceland, Denmark and Norway. Duration: Minimum 6 months. Prerequisites: Working knowledge (spoken and written) of English as well as in one or more Nordic languages, a basic knowledge of methods and theories used in social pharmacy. Suggested elective course: S-369 (Course in International Health Care) (held annually in the fall semester) For further information, please contact Janine Morgall Traulsen, Department of Pharmacology and Pharmacotherapy, Section for Social Pharmacy: jam@farma.ku.dk

B6. Consumerism in health care – focus on the medicine user Millions of people are forced to live with and manage chronic illnesses which are both troublesome and stigmatizing. At the same time, they are often afraid of losing control over symptoms while also being concerned about the long term side effects of medicines. This dilemma acts as a strong motive for trying to avoid conventional medicines and for seeking out alternatives. Recent studies show that most informants report that alternatives are no match for conventional medicines and they eventually come back to rely on the medicines they were attempting to find alternatives to. The choice of medicines is often reduced to a choice about what medicines to take, when and how, rather than whether or not to take it. In other words, no matter how informed they become, in the end patients are still dependent upon conventional medicines. The project will look at these issues in relation to notions on consumerism and the idea of lay re-skilling in response to dealing with the risks of everyday life. In order to provide a more nuanced characterization of the dilemmas and difficulties of living with chronic illness and the subsequent dependency on medicine, the project will explore the concept of ‘active dependence'. Duration: Minimum 6 months. Prerequisites: Working knowledge (spoken and written) of English, a basic knowledge of methods and theories used in social pharmacy.

Suggested elective course: S-369 (Course in International Health Care) (held annually in the fall semester) For further information, please contact Janine Morgall Traulsen, Department of Pharmacology and Pharmacotherapy, Section for Social Pharmacy: jam@farma.ku.dk B7. The community pharmacy sector – current and future trends This project will be a comparison between the community pharmacy sector in Denmark and one or more EU countries. The issues that will be addressed include: staffing, tasks performed, price mechanisms, personnel policy, prescribing pharmacists (supplementary or independent), pharmaceutical care etc Duration: Minimum 6 months. Prerequisites: Working knowledge (spoken and written) of English, a basic knowledge of methods and theories used in social pharmacy. Suggested elective course: S-369 (Course in International Health Care) (held annually in the fall semester) For further information, please contact Janine Morgall Traulsen, Department of Pharmacology and Pharmacotherapy, Section for Social Pharmacy: jam@farma.ku.dk B8. The labour/job market opportunities for pharmacists – A comparison between Denmark and one or more EU countries Whereas the majority of persons graduating with degrees in Pharmacy go into community pharmacy or hospital sector the opposite is true for Denmark. The majority of Danish pharmacists go to work in industry i.e. 60% of our graduates, whereas approximately 14% go into community pharmacy. Why is this so? How and when did this happen? What are the implications for pharmacy education? What are the implications for the pharmacy profession? Is this a European trend or just a Danish phenomenon? Duration: Minimum 6 months. Prerequisites: Working knowledge (spoken and written) of English, a basic knowledge of methods and theories used in social pharmacy. Suggested elective course: S-369 (Course in International Health Care) (held annually in the fall semester) For further information, please contact Janine Morgall Traulsen, Department of Pharmacology and Pharmacotherapy, Section for Social Pharmacy: jam@farma.ku.dk B9. Ethnic minority patients and the pharmacy The multi-ethnic society is a reality in a wide range of countries. Studies describing the relationship between etnicity and counselling in community pharmacy, though, are few. The student has to make a systematic review of the international literature on 1) the needs, views and experiences of ethnic minority patients of community pharmacy and medicines, 2) experiences on carrying out medication review with ethnic minority patients, 3) drug-related problems (type/frequency) as they are experienced by ethnic minority patients, 4) specific strategies and tools used for improving compliance among ethnic minority patients and/or 5) self-care medication practices of ethnic minority patients. The student will be associated a current project in the Section for Social Pharmacy, aiming at improving drug use among ethnic minorities. Duration: Minimum 6 months. Prerequisites: working knowledge (spoken and written) of English; a basic knowledge of methods and theories used in social pharmacy.

Suggested elective course: S-369 (Course in International Health Care) (held annually in the fall semester) For further information, please contact Lotte Stig Haugbølle, Department of Pharmacology and Pharmacotherapy, Section for Social Pharmacy: lsh@farma.ku.dk Projects at the Department of Medicinal Chemistry M1. Structure elucidation of natural products using hyphenated and non-hyphenated NMR techniques Natural products are important as potential pharmacological agents and tools and other bioactive entities, biomarkers, compounds affecting quality of plant products and other products of natural origin, scaffolds for syntheses, etc. While isolation and characterization of natural products has traditionally been a very laborious and lengthy process, on-line combination of HPLC separation with NMR (nuclear magnetic resonance spectroscopy) and MS (mass spectrometry) provides an opportunity of characterization of natural products in mixtures (extracts, fractions, various products of natural origin) without classical preparative-scale isolation. These so-called hyphenated techniques (HPLC-NMR and HPLC-MS) often bring very significant gains in terms of time and amount of material needed for the analysis. This project is a part of ongoing efforts in the field of development and applications of hyphenated NMR methods at this laboratory. Projects on structure elucidation of natural products by other modern NMR methods (non-hyphenated 2D NMR and microcoil NMR, for example in connection with bioactivity-guided fractionations) and non-natural products applications of hyphenated NMR techniques for pharmaceutical analysis are also possible. Duration of project: minimum of 6 months Prerequisites: Candidates should have prior knowledge of and interest in natural products, and theoretical as well as hands-on experience with 1D and 2D NMR spectroscopy and HPLC. For further information, please contact Jerzy W. Jaroszewski, jj@farma.ku.dk, Department of Medicinal Chemistry. M2. NMR-based metabolomics and metabonomics in natural products research and biomarker identification Classical chemical analysis focuses on characterization of a single or of a few components of a mixture. However, properties of many mixtures, e.g., foods and herbal medicines as well as other products of natural origin, are often determined by many constituents simultaneously or, alternatively, by yet unknown constituents. In such cases, non-target global analysis is advantageous. In metabolomics and matabonomics, quantification and characterization of as many components of a mixture as possible, in the latter case as a function of some kind of stimuli, is attempted. Because NMR spectroscopy is a non-selective detection technique with excellent resolving power, is it well suited for global characterization of complex mixtures. Projects in this area will consist of 1H NMR spectroscopic characterization of complex mixtures (typically plant products or body fluids) followed by multivariate analysis and pattern recognition techniques with the aim of determination of variances, group classification, and biomarker identification. Duration of project: minimum of 6 months Prerequisites: Candidates should have prior knowledge of theory and practice of NMR spectroscopy and basic knowledge of multivariate statistics. Knowledge of software for principal component analysis will be advantageous. For further information, please contact Jerzy W. Jaroszewski, jj@farma.ku.dk, or Nils T.

Nyberg, nn@farma.ku.dk, Department of Medicinal Chemistry. M3. Structure elucidation of natural products using hyphenated and non-hyphenated NMR techniques Natural products are important as potential pharmacological agents and tools and other bioactive entities, biomarkers, compounds affecting quality of plant products and other products of natural origin, scaffolds for syntheses, etc. While isolation and characterization of natural products has traditionally been a very laborious and lengthy process, on-line combination of HPLC separation with NMR (nuclear magnetic resonance spectroscopy) and MS (mass spectrometry) provides an opportunity of characterization of natural products in mixtures (extracts, fractions, various products of natural origin) without classical preparative-scale isolation. These so-called hyphenated techniques (HPLC-NMR and HPLC-MS) often bring very significant gains in terms of time and amount of material needed for the analysis. This project is a part of ongoing efforts in the field of development and applications of hyphenated NMR methods at this laboratory. Projects on structure elucidation of natural products by other modern NMR methods (non-hyphenated 2D NMR and microcoil NMR, for example in connection with bioactivity-guided fractionations) and non-natural products applications of hyphenated NMR techniques for pharmaceutical analysis are also possible. Duration of project: minimum of 6 months Prerequisites: Candidates should have prior knowledge of and interest in natural products, and theoretical as well as hands-on experience with 1D and 2D NMR spectroscopy and HPLC. For further information, please contact Jerzy W. Jaroszewski, jj@farma.ku.dk, Department of Medicinal Chemistry. M4. NMR-based metabolomics and metabonomics in natural products research and biomarker identification Classical chemical analysis focuses on characterization of a single or of a few components of a mixture. However, properties of many mixtures, e.g., foods and herbal medicines as well as other products of natural origin, are often determined by many constituents simultaneously or, alternatively, by yet unknown constituents. In such cases, non-target global analysis is advantageous. In metabolomics and matabonomics, quantification and characterization of as many components of a mixture as possible, in the latter case as a function of some kind of stimuli, is attempted. Because NMR spectroscopy is a non-selective detection technique with excellent resolving power, is it well suited for global characterization of complex mixtures. Projects in this area will consist of 1H NMR spectroscopic characterization of complex mixtures (typically plant products or body fluids) followed by multivariate analysis and pattern recognition techniques with the aim of determination of variances, group classification, and biomarker identification. Duration of project: minimum of 6 months Prerequisites: Candidates should have prior knowledge of theory and practice of NMR spectroscopy and basic knowledge of multivariate statistics. Knowledge of software for principal component analysis will be advantageous. For further information, please contact Jerzy W. Jaroszewski, jj@farma.ku.dk, or Nils T. Nyberg, nn@farma.ku.dk, Department of Medicinal Chemistry. M5. Natural product structure-activity relationships for lead optimization Natural products often are poor drugs either because of unwanted side effects, poor selectivity, problems with sustainable supply, or physical or chemical properties prohibiting efficient administration of the compound. Systematic structure-activity studies might enable design of a

compound with optimized properties. Projects in this area will focus on selective transformations of natural products or total synthesis of natural products or analogues using modern synthetic techniques. Duration of project: minimum of 6 months Prerequisites: Candidates should have a prior knowledge to organic synthetic techniques and basic knowledge of NMR spectroscopy. For further information, please contact S. Brøgger Christensen, sbc@farma.ku.dk, or Henrik Franzyk, hf@farma.ku.dk, Department of Medicinal Chemistry. M6. Polycationic antimicrobials Emergence of resistant bacteria is a serious health problem, and development of novel antibiotics is thus an urgent task within medicinal chemistry. The possible projects are aiming at the development of natural antimicrobials into promising leads. Improvement of pharmacological properties by structural modification for obtaining maximal antimicrobial activity and minimal hemolytic effect will be investigated. Amino acid replacement and/or deletions in natural short antimicrobial peptides from wasps or spiders constitute a possible project where the focus is on incorporation of designed unnatural residues, which confer enhanced stability towards proteases and allow for increased charge and control of overall lipophilicity – both important factors for antimicrobial activity. An important synthetic aspect is preparation of unnatural amino acid building blocks ready for solid-phase peptide synthesis of compound arrays for structure-activity studies of peptide analogues. It is intended to employ solution-phase aziridine chemistry for gram-scale preparation of selected amino acid building blocks. Duration of project: minimum of 6 months Prerequisites: Candidates should have prior knowledge of and interest in peptide chemistry or solid-phase synthesis. Theoretical as well as hands-on experience with microwave-assisted organic chemistry, HPLC as well as NMR spectroscopy is an advantage. For further information, please contact Henrik Franzyk, hf@farma.ku.dk, Department of Medicinal Chemistry. M7. Structure determination of the ligand-binding core of the ionotropic glutamate receptors in order to understand the selectivity observed for ligands. Successful structure determinations of the ligand-binding core of different subtypes of ionotropic glutamate receptors have been performed during the last ten years. The structures describe complexes between the ligand-binding core of the receptors and either an agonist, an antagonist or an allosteric modulator. Different subtypes of the ionotropic glutamate receptors are available; AMPA receptors: iGluR2 and iGluR4, kainate receptors: iGluR5 and iGluR6, as well as the Delta 2 receptor. The known structures have provided valuable information on interaction mode for the various ligands with the different receptor subtypes, as well as information on the mechanism of activation and antagonism. The aim of this project is to determine the structure of new ligands in complex with the ligand-binding cores from two different subtypes of ionotropic glutamate receptors in order to study selectivity. The project includes crystallization of the ligand-binding core with new ligands, followed by x-ray data collection. Hereafter, structure determination and refinement, as well as analysis of the structure, will be performed using computer-based methods. Duration of the project: 4-6 months For further information, please contact Karla Frydenvang kf@farma.ku.dk or Jette Sandholm Kastrup jsk@farma.ku.dk, Department of Medicinal Chemistry.

M8. Structure determination of a double mutant of the ionotropic glutamate receptor iGluR2 (Leu483Tyr,Asn754Ser) in order to characterize the binding of a new type of dimeric positive allosteric modulators A new type of dimeric positive allosteric modulators for ionotropic glutamate receptors has recently been designed, synthesized and pharmacologically characterized by electrophysiology. The designed compounds are dimers of arylpropyl-sulfonamides. The monomeric arylpropyl-sulfonamides were designed from known modulators in order to achieve binding to the cyclothiazide binding site on AMPA receptors. The biarylpropyl-sulfonamides reveal much higher potencies compared to the corresponding monomers. One dimeric modulator have been co-crystallized with the ligand-binding core of iGluR2, and the x-ray structure determination has revealed that the modulator cross-links two identical binding sites on two neighboring iGluR2 molecules. The aim of the project is to explain the much higher potency of dimeric modulators compared to the corresponding monomers. The project includes crystallization of the double mutant (Leu483Tyr,Asn754Ser) of the ligand-binding core of iGluR2 with new allosteric modulators followed by structure determination and analysis using computer-based methods. It is characteristic for this double mutant that it forms well-defined dimers in solution. This makes it possible to perform detailed studies of ligand binding (dimer compared to monomer) using isothermal titration calorimetry (ITC), which will also be a part of the project. From ITC, knowledge is gained on whether binding is driven by enthalpy or entropy. Duration of the project: 4-6 months For further information, please contact Jette Sandholm Kastrup jsk@farma.ku.dk, Karla Frydenvang kf@farma.ku.dk or Lars Olsen lo@farma.ku.dk, Department of Medicinal Chemistry.

M9. Design and synthesis of potential subtype selective ligands for the GABAA or nicotinic acetylcholine receptors The GABAA and nicotinic acetylcholine (nACh) receptors, which structural are very similar, are both important drug targets in a number of neurological and psychiatric disorders such as Alzheimer’s Disease, Parkinson’s Disease, epilepsy, schizophrenia and depression. There exist a number of subtypes within each of the receptor groups differentiating in amino acid sequence, regional location and function. This open up for subtype selective targeting, and thereby development of ligands with potential optimised therapeutic properties. Since no 3D-structure of the GABAA and nACh receptors has been reported, our studies are based on homology receptor models and structure-activity studies of known ligands mainly developed at FARMA. This project is aimed at design and synthesis of potential subtype selective ligands to be used for exploring the binding pockets of the receptors, in search for the structural basis for subtype selective targeting. This is done in close collaboration with colleagues mastering molecular modelling and molecular pharmacology at FARMA. For the student the present project will involve experimental organic synthesis, spectroscopic characterisation and structure-activity studies. No. of students: 1-2 students Duration: 6-12 months Prerequisites: Basic experimental organic synthesis experience will be a prerequisite for the project.

For further information, please contact Bente Frølund, Department of Medicinal Chemistry, bfr@farma.ku.dk

in silico Metabolism - Classification of Cytochrome P450 Ligands Lars Olsena, Poongavanam Vasanthanathana, Olivier Taboureaua,b and Flemming Steen Jørgensena

aDepartment of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copanhagen bCenter for Biological Sequence Analysis, BioCentrum-DTU, Technical University of Denmark &

The cytochrome P450 (CYP) superfamily plays an important role in the metabolism of drug compounds, and it is therefore highly desirable to have models that can predict whether a compounds interacts with a specific isoform of the CYP's. Recently, we have develop an in silico model for classification of CYP1A2 inhibitors and non-inhibitors. The model is based on a large dataset of 8342 compounds from PubChem tested for activity for the CYP1A2 enzyme. We divided the data set in a representative training set and a large diverse test set, calculated both simple 2D descriptors (e.g. MW, clogP, atom and bond counts) and sophisticated 3D descriptors derived from molecular interaction fields (e.g. VolSurf descriptors) for all the compounds, and developed classification models based on various methods. The methods include modern statistical methods like projections of latent variables by least-squares methods (PLS) and self-organising maps (SOM), but also simple decision-tree models like the one outlined below.

PubChem also contains large datasets for CYP2C9, CYP2C19, CYP2D6 and CYP3A4 ligands. In the present project, we would like to apply the procedure proven to be successful for the CYP1A2 ligands to the other isoforms. First, it would be interesting to develop individual models for each of the isoform, but it would also be challenging to develop one model being able to predict the selectivity between the different isoforms. The project is highly relevant for industry in order to avoid Adverse Drug Effects (ADE), known to be a major problem for the development of new drugs. The project is a collaborative project between KU-FARMA and DTU. The project is suitable for 1-2 students for a half-year speciale project. Contact Lars Olsen (building 30, room 113, phone = 3533 6305 or mail = lo@farma.ku.dk) for more details.

More information: David Gloriam, building 30, room 109, phone 3533 6162 or email=dg@farma.ku.dk

Do you want to design a drug using computer-based methods?

- Computer-based design of focused compound libraries for G protein-coupled receptors

David Gloriama, Olivier Taboureaua,b and Flemming Steen Jorgensena

aDepartment of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen bCenter for Biological Sequence Analysis, BioCentrum-DTU, Technical University of Denmark

Aim: The aim of this project is to design GPCR-targeted focused compound libraries which can be used to identify new GPCR ligands that can become important research tools. Background: G protein-coupled receptors (GPCRs) are among the most important drug targets. It is estimated that 50% of drugs presently on the market exert their activity by interaction via a GPCR. Ligands for GPCRs can be very structurally diverse and new ligands can have the potential to become important research tools or drugs (in industry).

Computer-based methodology for focused compound library design: Ligand-based methodology: Ligand-based methods use a known ligand structure when trying to find an improved structure which might be a suitable drug. Imagine you have a lock and a key that almost fits and you try to design a new key that can open the lock. Examples of techniques are compound similarity searches and pharmacophore searches. Target-based methodology: Target-based methods use the protein structure in the search for ligands, which may have affinity to it. Imagine you have the lock but no key and you try to design the key by closely study the lock. Example of techniques are virtual screening of a receptor structure model and combinatorial fragment-based ligand design based on a target pharmacophore.

3D model of a GPCR with a ligand bound at the top.

Examples of GPCR ligands.

Characterization of GPCR Ligands by Chemoinformatics

David Gloriama, Olivier Taboureaua,b and Flemming Steen Jørgensena aDepartment of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copanhagen

bCenter for Biological Sequence Analysis, BioCentrum-DTU, Technical University of Denmark & G-Protein coupled receptors (GPCRs) represent one of the most important classes of drug targets. It is estimated that 50% of the drugs presently on the market exert their activity by interaction via a GPCR. Ligands for GPCRs comprise structurally very different compounds and often the ligands interact with more than one GPCR – They are promiscuous. The aim of this project is to develop a method for classification of GPCR ligands, i.e. to predict which GPCR a ligand is most likely to interact with. The method will be based entirely on the structure of the ligands in order to be able to classify ligands prior to their preparation (virtual screening). We believe that the method will be a valuable tool for evaluation and selection of ligands for subsequent preparation and biological testing in the drug discovery process.

The experimental data for this project will be extracted from the WOMBAT (WOrld of Molecular BioAcTivity) database from Sunset Molecular Discovery, which contains more than 40.000 GPCRs. For each of the relevant biological end-points (e.g. serotonin, dopamine, noradrenalin etc.) a structurally diverse and representative dataset will be extracted. Each of these dataset should be sufficiently large to reflect the diversity of the compounds within the class. For all the compounds in the different classes molecular descriptors will be calculated. The descriptors will include simple 2D descriptors (e.g. MW, clogP, atom and bond counts) as well as sophisticated 3D descriptors derived from molecular interaction fields (e.g. VolSurf descriptors). For the classification models methods like principal component analysis (PCA), projections of latent variables by least-squares methods (PLS), self-organising maps (SOM) and annotated neural networks (ANN) will be applied. Finally, the models will be evaluated by classification of an independently selected test set of ligands. As an ultimate goal the models should be used for prediction of GPCR activity for yet untested compounds. The individual steps in the project are illustrated in the above figure. The review by Klabunde and Hessler, ChemBioChem 3 (2002) provides an excelent introduction to the topic. The project is a collaborative project between KU-FARMA and DTU. The project is suitable for 1-2 students for a half-year speciale project. Contact David Gloriam (building 30, room 109, phone = 3533 6162 or mail = dg@farma.ku.dk) for more details.

F A C U L T Y O F P H A R M A C E U T I C A L S C I E N C E S U N I V E R S I T Y O F C O P E N H A G E N

Available MSc Project “SYNTHESIS OF NOVEL LIGANDS WHICH TARGET THE GLUTAMATERGIC NEUROTRANSMITTER SYSTEM IN THE BRAIN” Question: Are you interested in organic / medicinal chemistry? Answer: Join us to uncover tomorrow’s medicines for brain diseases.

Question: Why target the glutamatergic neurotransmitter system? Answer: The neurotransmitter glutamate (Glu) is involved in important neuro-physiological processes such as memory and learning, motor functions, and neural plasticity and development. Therefore, it is believed that brain diseases such as Alzheimer’s disease, Huntington’s disease, amyotrophic lateral sclerosis, epilepsy, depression, anxiety, schizophrenia and cerebral stroke may be directly related to disordered glutamatergic neurotransmission. To study the detailed function of the Glu receptors and transporters, we develop subtype selective ligands. In collaboration with pharmacologists our synthesized compounds are investigated carefully both in-vitro and in-vivo.

For further information, please contact:

Lennart Bunch, Associate Professor, PhD

Email: lebu@farma.ku.dk. Phone: 35 33 62 44 Homepage: www.farma.ku.dk/index.php?id=497

Info: Duration: 45-60 ECTS points

Start: As agreed to

Project outline: Retro-synthetic analysis

Literature study Experimental organic chemistry

Report writing / publication