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Contenu archivé le 2024-05-14

Inverse agonism. Implications for drug design


- The generation of constitutively active and inactive mutant receptors(CAMs and CIMs, respectively) expressed in suitable cell systems.
- The generation of transgenic mice with various levels of wild type and mutant receptor expression.
- The selection and testing of agonists, (neutral) antagonists, and inverse agonists with the tools under 1) and 2)
- The synthesis of a set of compounds based on previously determined structure-intrinsic activity relationships and 3D receptor models.
- The organisation of a consensus meeting at the end of the proposal's term provide the scientific and industrial community with a scientific rationale and evaluation of the concept of inverse agonism.

G protein-coupled receptors (GPCRs) are the target in the human body for many of today' s medicines. Almost all European pharmaceutical companies market drugs that are GPCR agonists and antagonists aimed at diverse disease states such as hypertension, asthma, anxiety and depression. Current dogma is that the efficacy of these drugs is thought to be a continuum ranging from low values for competitive .antagonists to higher values for agonists. Recently, however, this experimental and theoretical concept has been firmly challenged. Under various experimental conditions antagonists may display 'negative efficacy'. Such compounds have been referred to as 'inverse agonists'.
The central theme of the project (InverseA) concerns the debate whether 'inverse agonism' is to be regarded as a novel concept for the design and development of new chemical entities (NCEs) rather than as a pharmacological curiosity peculiar to genetically-engineered experimental systems. It is the participants' ambition to address this matter with the specific aim of providing a scientific rationale for the assessment of claims that pertain to existing drugs and NCEs as potential 'inverse agonists'. This is of particular relevance to the European Patent Office as well as the European Medicines Evaluation Agency. Since the principle has also been demonstrated for drugs already on the market, the proposal and its outcome may also affect current thinking among clinicians, with immediate impact on pharmacotherapeutic intervention in patients.
It is obvious that this new concept in receptor theory will evoke a strong interest from pharmaceutical companies with the potential danger of duplication of efforts, manpower and funds. Therefore, an industrial platform has been set up in parallel to this research proposal, to function as a sounding board for the planned research activities. Second, wide and rapid dissemination of results will be assured by deposition of the findings in the EU-sponsored GPCR database maintained at EMBL/EBI (Heidelberg, Hinxton). Letters of acceptance and recommendation from companies and EMBL are in ANNEX 1 to the proposal.

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