Karsten Menzel

Mechanism based neurotoxicity of mGlu5 positive allosteric modulators – Development challenges for a promising novel antipsychotic target

Previous work has suggested that activation of mGlu5 receptor augments NMDA receptor function and thereby may constitute a rational approach addressing glutamate hypofunction in schizophrenia and a target for novel antipsychotic drug development. Here, we report the in vitro activity, in vivo efficacy and safety profile of 5PAM523 (4-Fluorophenyl){(2R,5S)-5-[5-(5-fluoropyridin-2-yl)-1,2,4-oxadiazol-3-yl]-2-methylpiperidin-1-yl}methanone), a structurally novel positive allosteric modulator selective of mGlu5. In cells expressing human mGlu5 receptor, 5PAM523 potentiated threshold responses to glutamate in fluorometric calcium assays, but does not have any intrinsic agonist activity. 5PAM523 acts as an allosteric modulator as suggested by the binding studies showing that 5PAM523 did not displace the binding of the orthosteric ligand quisqualic acid, but did partially compete with the negative allosteric modulator, MPyEP. In vivo, 5PAM523 reversed amphetamine-induced locomotor activity in rats. Therefore, both the in vitro and in vivo data demonstrate that 5PAM523 acts as a selective mGlu5 PAM and exhibits anti-psychotic like activity. To study the potential for adverse effects and particularly neurotoxicity, brain histopathological exams were performed in rats treated for 4 days with 5PAM523 or vehicle. The brain exam revealed moderate to severe neuronal necrosis in the rats treated with the doses of 30 and 50 mg/kg, particularly in the auditory cortex and hippocampus. To investigate whether this neurotoxicity is mechanism specific to 5PAM523, similar safety studies were carried out with three other structurally distinct selective mGlu5 PAMs. Results revealed a comparable pattern of neuronal cell death. Finally, 5PAM523 was tested in mGlu5 knock-out (KO) and wild type (WT) mice. mGlu5 WT mice treated with 5PAM523 for 4 days at 100 mg/kg presented significant neuronal death in the auditory cortex and hippocampus. Conversely, mGlu5 KO mice did not show any neuronal loss by histopathology, suggesting that enhancement of mGlu5 function is responsible for the toxicity of 5PAM523. This study reveals for the first time that augmentation of mGlu5 function with selective allosteric modulators results in neurotoxicity.

Mining building performance data for energy-efficient operation

Abstract This research investigates the impact of connecting building characteristics and designs with its performance by data mining techniques, hence the appropriateness of a room in relation to energy efficiency. Mining models are developed by the use of comparable analytical methods. Performance of prediction models is estimated by cross validation consisting of holding a fraction of observations out as a test set. The derived results show the high accuracy and reliability of these techniques in predicting low-energy comfortable rooms. The results are extended to show the benefits of these techniques in optimizing a building’s four basic elements (structure, systems, services and management) and the interrelationships between them. These techniques extend and enhance, current methodologies, to simplify modeling interior daylight and thermal comfort, to further assist building energy management decision-making.

Towards a wireless sensor platform for energy efficient building operation

Abstract Currently, the IT-support for energy performance rating of buildings is insufficient. So-called IT-platforms often “built” of an ad-hoc, inconsistent combination of off-the-shelf building management components, distributed data metering equipment and several monitoring software tools. A promising approach to achieve consistent, holistic performance data management is the implementation of an integrated, modular wireless sensor platform. This paper presents an approach of how wireless sensors can be seamlessly integrated into existing and future intelligent building management systems supporting improved building performance and diagnostics with an emphasis on energy management.

Tricyclic imidazole antagonists of the Neuropeptide S Receptor

A new structural class of potent antagonists of the Neuropeptide S Receptor (NPSR) is reported. High-throughput screening identified a tricyclic imidazole antagonist of NPSR, and medicinal chemistry optimization of this structure was undertaken to improve potency against the receptor as well as CNS penetration. Detailed herein are synthetic and medicinal chemistry studies that led to the identification of antagonists 15 and NPSR-PI1, which demonstrate potent in vitro NPSR antagonism and central exposure in vivo.

Potentials for Radio Frequency Identification in AEC/FM

Radio frequency identification (RFID) technology has proved to be very effective in industries as diverse as aircraft manufacturing to health and care. The construction industry has been slow to take up on RFID and this paper will discuss the merits of the technology in its potential for application within the construction sector. The paper reports about the prototypical implementation of RFID-based information management in FM-scenarios. The prototypes were tested at University College Cork (UCC). The general applicability of RFID for decentralised information management could be demonstrated.

Novel oxazolidinone calcitonin gene-related peptide (CGRP) receptor antagonists for the acute treatment of migraine

In our efforts to develop CGRP receptor antagonists as backups to MK-3207, 2, we employed a scaffold hopping approach to identify a series of novel oxazolidinone-based compounds. The development of a structurally diverse, potent (20, cAMP+HS IC50=0.67 nM), and selective compound (hERG IC50=19 μM) with favorable rodent pharmacokinetics (F=100%, t1/2=7h) is described. Key to this development was identification of a 3-substituted spirotetrahydropyran ring that afforded a substantial gain in potency (10 to 35-fold).

Novel Cytochrome P450-Mediated Ring Opening of the 1,3,4-Oxadiazole in Setileuton, a 5-Lipoxygenase Inhibitor

Setileuton [4-(4-fluorophenyl)-7-[({5-[(1S)-1-hydroxy-1-(trifluoromethyl)propyl]-1,3,4-oxadiazol-2-yl}amino)methyl]-2H-1-benzopyran-2-one] is a selective inhibitor of the 5-lipoxygenase enzyme, which is under investigation for the treatment of asthma and atherosclerosis. During the development of setileuton, a metabolite (M5) was identified in incubations with rat, dog, and human liver microsomes that represented the addition of 18 Da to the 1,3,4-oxadiazole portion of the molecule. Based on mass spectral data, a ring opened structure was proposed and confirmed through comparison with a synthetic standard. The metabolic ring opening was examined in vitro in rat liver microsomes and was determined to be mediated by cytochrome P450s (P450s). Upon examination of the specific P450s involved using cDNA-expressed rat P450s, it was shown that CYP1A2 likely was the major isoform contributing to the formation of M5. Studies using stable labeled molecular oxygen and water demonstrated that the oxygen was incorporated from molecular oxygen, rather than water, and confirmed that the metabolic formation was oxidative. An alternative, comparatively slow pathway of chemical hydrolysis also was identified and described. Three potential mechanisms for the two-step metabolic ring opening of the 1,3,4-oxadizole are proposed.

Decision Support for Building Renovation Strategies

The renovation of existing buildings usually involves decision-making processes aiming at reducing energy consumption and building maintenance costs. The goal of this paper is to prioritize what components/systems need to be replaced. It focuses on renovation strategies from the maintenance density and energy consumption point of view. A Decision Support Framework (DSF) was developed for future development of Decision Support System. Data warehousing methodologies were used to extract, store and analyze maintenance data. A Web application was developed to display the frequency of faults and density of maintenance of six distinct buildings at University College Cork (UCC). A generic Decision Support Model (DSM) with six sections was developed, which was implemented to a computerized semi-automatic tool – Decision Support Tool (DST). Integrating the analysis results and the DST, five renovation suggestions were proposed.

Towards a Meta-Model for Collaborative Construction Project Management

Projects in the building industry are extremely dynamic and affected by several constraints. Therefore, common principles should be established throughout the construction industry that allows flexibly specifying and combining construction project information for the inter-organisational collaboration. New members should be supported to join and leave the project consortium by providing them with all relevant project information. Consequently, there is a need for an overall model representing the different design, construction and management activities as well as the building objects, organisational and IT infrastructure of the project. The paper presents an approach towards a common meta-model for collaborative construction process management. Relevant construction project constraints will be identified and classified in order to develop a Construction Network Meta-Model. Furthermore, a Framework for the instantiation of Construction Networks will be introduced.

RFID based Efficient Lighting Control

The Kyoto Protocol and the European Energy Performance of Buildings Directive put an onus on governments and organisations to lower carbon footprint in order to contribute towards reducing global warming. A key parameter to be considered in buildings towards energy and cost savings is its indoor lighting that has a major impact on overall energy usage and Carbon Dioxide emissions. Lighting control in buildings using Passive Infrared sensors is a reliable and well established approach; however, the use of only Passive Infrared does not offer much savings towards reducing carbon, energy, and cost. Accurate occupancy monitoring information can greatly affect a building’s lighting control strategy towards a greener usage. This paper presents an approach for data fusion of Passive Infrared sensors and passive Radio Frequency Identification (RFID) based occupancy monitoring. The idea is to have efficient, need-based, and reliable control of lighting towards a green indoor environment, all while considering visual comfort of occupants. The proposed approach provides an estimated 13% electrical energy savings in one open-plan office of a University building in one working day. Practical implementation of RFID gateways provide real-world occupancy profiling data to be fused with Passive Infrared sensing towards analysis and improvement of building lighting usage and control.