Analysis of molecular determinants of affinity and relative efficacy of a series of R- and S-2-(dipropylamino)tetralins at the 5-HT1A serotonin receptor

1 Factors influencing agonist affinity and relative efficacy have been studied for the 5-HT1A serotonin receptor using membranes of CHO cells expressing the human form of the receptor and a series of R-and S-2-(dipropylamino)tetralins (nonhydroxylated and monohydroxylated (5-OH, 6-OH, 7-OH, 8-OH) species). 2 Ligand binding studies were used to determine dissociation constants for agonist binding to the 5HT(1A) receptor: (a) K-i values for agonists were determined in competition versus the binding of the agonist [H-3]-8-OH DPAT. Competition data were all fitted best by a one-binding site model. (b) K-i values for agonists were also determined in competition versus the binding of the antagonist [H-3]-NAD-199. Competition data were all fitted best by a two-binding site model, and agonist affinities for the higher (K-h) and lower affinity (K-1) sites were determined. 3 The ability of the agonists to activate the 5-HT1A receptor was determined using stimulation of [S-35]-GTPgammaS binding. Maximal effects of agonists (E-max) and their potencies (EC50) were determined from concentration/response curves for stimulation of [S-35]-GTPgammaS binding. 4 K-1/K-h determined from ligand binding assays correlated with the relative efficacy (relative Em) of agonists determined in [S-35]-GTPgammaS binding assays. There was also a correlation between K-1/K-h and K-1/EC50 for agonists determined from ligand binding and [S-35]-GTPgammaS binding assays. 5 Simulations of agonist binding and effect data were performed using the Ternary Complex Model in order to assess the use of K-1/K-h for predicting the relative efficacy of agonists. British Journal of Pharmacology (2003) 138, 1129-1139. doi: 10. 1038/sj.bjp.705085.

Interaction of the D-2short dopamine receptor with G proteins: analysis of receptor G protein selectivity

The human D-2short (D-2S) dopamine receptor has been expressed together with the G proteins Gi2 and Go in insect cells using the baculovirus system. Levels of receptor were determined using [H-3]spiperone binding. Levels of G protein heterotrimer were determined using quantitative Western blot and using [S-35]GTPgammaS saturation binding experiments. Levels of the receptor and G protein and the receptor/G protein ratio were similar in the two preparations. Stimulation of [S-35]GTPgammaS binding by a range of agonists occurred with higher relative efficacy and in some cases higher potency in the preparation expressing Go, indicating that interaction of the D-2S receptor is more efficient with this G protein. The effects of various G protein-selective agents on 10,11-dihydroxy-N-n-propylnorapomorphine ([H-3]NPA) binding were used to examine the receptor/G protein complex in the two preparations. Suramin inhibited [H-3]NPA binding with slightly higher potency in the Gi2 preparation, whereas GppNHp inhibited [H-3]NPA binding with greater potency (similar to6-fold) in the Go preparation. This may imply that the G protein is more readily activated in the D-2S/Go preparation. [H-3]Spiperone binding occurred with an increased B-max in the presence of suramin in the Go preparation but not in the Gi2 preparation, suggesting a higher affinity interaction between the free receptor and this G protein. It is concluded that the higher efficiency activation of Go by the D-2S receptor may be a function of higher affinity receptor/G protein interaction as well as a greater ability to activate the G protein. (C) 2003 Elsevier Science Inc. All rights reserved.

A review of the use of demonstration projects to achieve widespread adoption of innovative practices

The UK construction industry has embarked on one of the largest experiments in the implementation of innovative technologies and practices in its history. Following Rethinking Construction[1], generally known as the Egan Report, the Movement for Innovation was established with the aim of using demonstration projects as practical examples of innovation in order to encourage others to follow the example. The number of demonstration projects has exceeded the original plans and more are being added. This paper reviews the approach in terms of the practice of using demonstration projects to achieve widespread take up of innovation, the modifications to the programme and its management and considers future developments to improve its, effectiveness.

Implementation of VR systems: a comparison between the early adoption of CAD and current uptake of VR

Use of new technologies, such as virtual reality (VR), is important to corporations, yet understanding of their successful implementation is insuf. ciently developed. In this paper a case study is used to analyse the introduction of VR use in a British housebuilding company. Although the implementation was not successful in the manner initially anticipated, the study provides insight into the process of change, the constraints that inhibit implementation and the relationship between new technology and work organization. Comparison is made with the early use of CAD and similarities and differences between empirical . ndings of the case study and the previous literature are discussed.

Consequences of a coexistence policy on the adoption of GMHT crops in the European Union

This article examines the adoption of genetically modified herbicide tolerant (GMHT) crops in the European Union (EU) prior to its commercial release. A set of potential drivers including the implementation of coexistence measures by farmers, farmers’ own motivational factors (e.g. economic, environmental and technical factors) and perceived social pressure to accept or reject adoption may influence European Union farmers’ willingness to adopt GMHT oilseed rape and GMHT maize. The analysis includes economic and sociological factors. Results show that coexistence measures may hamper GMHT adoption in the EU.

Adoption of ICT among small business: vision vs. reality

The aim of this paper is to present a case study of the adoption of Information and Communication Technologies (ICT) among 6000 small businesses within a locality of Greater Manchester, England. The paper presents an analysis of factors affecting adoption and discusses the wider implications for achieving the European vision of regional 'digital ecosystems".

The economic theory of international business: a supply chain perspective

This paper proposes a way of addressing unresolved issues in international business theory by modelling the multinational enterprise as a coordinator of supply chains. It identifies a new market seeking strategy that is an alternative to conventional strategies such as exporting, licensing and FDI, and analyses the conditions under which it will be adopted by firms. The new strategy involves the off-shoring of production and the out-sourcing of R&D, and is implemented through co-operation between a source country firm and a host country firm.

A socio-technical network approach to the adoption of low and zero carbon technologies in new housing

Housing in the UK accounts for 30.5% of all energy consumed and is responsible for 25% of all carbon emissions. The UK Government’s Code for Sustainable Homes requires all new homes to be zero carbon by 2016. The development and widespread diffusion of low and zero carbon (LZC) technologies is recognised as being a key solution for housing developers to deliver against this zero-carbon agenda. The innovation challenge to design and incorporate these technologies into housing developers’ standard design and production templates will usher in significant technical and commercial risks. In this paper we report early results from an ongoing Engineering and Physical Sciences Research Council project looking at the innovation logic and trajectory of LZC technologies in new housing. The principal theoretical lens for the research is the socio-technical network approach which considers actors’ interests and interpretative flexibilities of technologies and how they negotiate and reproduce ‘acting spaces’ to shape, in this case, the selection and adoption of LZC technologies. The initial findings are revealing the form and operation of the technology networks around new housing developments as being very complex, involving a range of actors and viewpoints that vary for each housing development.

Extending feature usage: a study of the post-adoption of electronic medical records

Technology Acceptance Model (TAM) posits that Perceived Ease of Use (PEOU) and Perceived Usefulness (PU) influence the ‘intention to use’. The Post-Acceptance Model (PAM) posits that continued use is influenced by prior experience. In order to study the factors that influence how professionals use complex systems, we create a tentative research model that builds on PAM and TAM. Specifically we include PEOU and the construct ‘Professional Association Guidance’. We postulate that feature usage is enhanced when professional associations influence PU by highlighting additional benefits. We explore the theory in the context of post-adoption use of Electronic Medical Records (EMRs) by primary care physicians in Ontario. The methodology can be extended to other professional environments and we suggest directions for future research.