The present proposal aims at the development of new compounds which can be used for the prevention and treatment of opioid, cocaine and alcohol addiction. This represents a new and innovative approach.Opioid receptors are heterogeneous, consisting of at least three major types ( m, d and k) with different ligand selectivity profiles, and mediate district pharmacological effects. Neither endogenous opioids nor synthetic ligands possess absolute specificity for a certain receptor type. Very active and very selective opioids are essential in the opioid basic research and in the medicinal treatment to prevent side effects.The strategy for the development of new potent and receptor selective opioid peptides is based on the concept of conformational restriction. Since small linear peptides are too flexible, the conformational restriction increases the rigidity of the molecules leading to more selective opioids. This concept requires the use of unnatural amino acids with defined topology in the design of opioid peptides.Flemish and Hungarian partners will develop new delta opioid agonist and antagonist in cold and radioactive forms. For this purpose several unnatural amino acids will be synthesized and used in the peptide synthesis. Analytical procedures will be developed for the purification of amino acids and peptides. Enzymatic and chiral chromatographic methods will be used to control the optical purities of amino acids and the configurations of unnatural amino acids in diastereomeric peptides.The newly developed peptides will be tested for receptor affinity and selectivity using radioreceptor assays. Their stability will be studied by incubation with enzymes and in brain homogenate and blood serum. HPLC/MS and CZE/MS will be used to identify the fragments. From the best compounds radioactive ligands will be prepared and tested in further biochemical assays.High field 2-dimensional NMR studies will be carried out in order to investigate the influence of the unnatural amino acid substitution on the topology of the peptides. These studies will be completed by molecular modeling.The Flemish and Hungarian partners have a long term research program which resulted in many publications and in synthesis methods applied in industry.
|Effective start/end date||20/12/96 → 19/06/00|
Flemish discipline codes
- Biological sciences
- delta opioid peptide ligands