Objective Foreseen ResultsIn this project a novel approach of effect-directed drug design in used to fill this gap. This approach is based on a non-exclusive model of agonist and antagonist interaction with receptor; its combination with quantitative structure-activity analysis allows prediction of the type of ligand action (agonist, antagonist or partial agonist). In this project we will express a series of the recombinant P2Y receptors in cell lines, in which the activation of these receptors is coupled to intracellular Ca2+- mobilization. The dose-response relationships of receptor activation can thus be determinated by means of fluorescence measurements to detect Ca2+mobilization. This assay system enables rapid screening of ligands and will be used for systematic studies of ligand-binding specificity of these receptor subtypes, analyzed proceeding from the modified receptor concept. Following the results of these studies new types of purinoceptor ligands will be developed, including nucleoside-coupled peptides. Screening of the activity of these ligands will be made by using synthetic combinatorial libraries, based on randomization of either the peptide or nucleotide parts of these compounds.A regulatory function of nucleotide (ATP, UMP,ADP, etc), interacting as extracellular transmitter through specific nucleotide receptors ("P2 purinoceptors") has been discovered recently and was finally established by the DNA-cloning of some of these receptors. It is becoming evident that purinergic receptors may present a novel amplification mechanism, strengthening the cellular responses in situations of crisis. This is exemplified by the platelet aggregation reaction where release of nucleotide (ADP) from one platelet activates and recruits hundred of other platelets, thus rapidly initiating blood clotting. It is obvious that such amplification is augmented in pathological conditions and the appropriate regulatory system is a potential target for drug, action, directed towards mechanisms which are primarily pathologic. Numerous in vitro and some in vivo studies have indicated that ATP is a co-transmitter in adrenergic neurones, where blocking of purinergic receptors attenuates sympathetic adrenergic responses. Thus, cardiovascular therapy directed against adrenergic receptors should be either potentiated or inhibited by P2 purinoceptor antagonists. For all of these reasons, therefore, that class of drug could be a new perspective for therapeutics for such diseases as hypertension, myocardial ischemia, and thrombosis. Developments in this area, are however, hampered by the lack of effective and subtype-specific antagonists of P2 receptors. Fields of science medical and health sciencesclinical medicineangiologyvascular diseasesmedical and health sciencesbasic medicinemedicinal chemistrynatural sciencesbiological sciencesbiochemistrybiomoleculesnatural sciencesbiological sciencesgeneticsnucleotides Programme(s) FP4-INCO - Specific research, technological development and demonstration programme in the field of cooperation with third countries and international organizations, 1994-1998 Topic(s) 01020903 - Application of biotechnologies in the development of vaccines, diagnostics and therapeutics Call for proposal Data not available Funding Scheme CSC - Cost-sharing contracts Coordinator AABO AKADEMI UNIVERSITY EU contribution No data Address 3,Tykistoekatu 6A 20521 TURKU / ABO Finland See on map Total cost No data Participants (3) Sort alphabetically Sort by EU Contribution Expand all Collapse all QSAR Foundation Hungary EU contribution No data Address 5,Hollan E. 5 1136 Budapest See on map Total cost No data Royal Free and University College Medical School Of University College London United Kingdom EU contribution No data Address Rowland Hill Street NW3 2PF London See on map Total cost No data UNIVERSITY OF TARTU Estonia EU contribution No data Address 2,Jakobi Street 2 51014 TARTU See on map Total cost No data
