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General Research Concept
Current research activities of the laboratory are primarily in the area of peptide hormones and neurotransmitters, whereby the major focus is on structure (conformation) - activity relationships, molecular details of peptide-receptor interactions and fundamental issues in peptide molecular pharmacology. As an extension of this fundamental research, efforts are also being made to develop new concepts in the design of peptide-derived drugs for possible therapeutic applications (including peptidomimetics).

To achieve these goals, an interdisciplinary research approach based on the combined and integrated use of organic chemistry, peptide synthesis, pharmacological testing and conformational studies is taken. Unusual (artificial) amino acids and peptidomimetic structural elements are synthesized and incorporated into peptides with the goal of developing highly specific pharmacological tools or potential drugs. For the determination of the biological activity profiles we use a battery of test systems, including receptor binding assays, bioassays using cultured cells, isolated tissue assays and in vivo assays. The conformations of the peptides and peptidomimetics are studied by NMR spectroscopy (400 and 600 MHz) and by theoretical conformational analysis (molecular mechanics studies, molecular dynamics simulations and receptor docking studies).

Peptides which have been primarily studied in recent years are the opioid peptides and antioxidant peptides.

Opioid peptides
In the past few years we have developed a number of prototype opioid receptor ligands that are of considerable interest as pharmacological tools and/or as potential drugs.

Very important was the discovery of a novel, potent delta opioid receptor peptide antagonist, H-Tyr-Tic-Phe-Phe-OH (TIPP), which displayed extraordinary delta selectivity and, unlike other delta antagonists, showed no mu or kappa antagonist properties. A pseudopeptide analog of TIPP, H-Tyr-Ticpsi[CH2-NH]Phe-Phe-OH (TIPP[psi]), was completely stable against chemical/enzymatic degradation, showed unprecedented delta selectivity and is widely used as a pharmacological tool in opioid research. The tripeptide analog H-Tyr-Ticpsi[CH2-NH]Phe-OH (TIP[psi]) also was a potent and selective delta antagonist. Conformational studies of TIP[psi] were performed by NMR spectroscopy in conjunction with theoretical conformational analyses. Recently, we tested these delta antagonists in a GTPase assay using cultured neuroblastoma x glioma (NG 108-15) hybrid cells that contain delta receptors. TIPP and TIPP[psi] were found to be neutral delta antagonists, whereas the TIPP analogs H-Dmt-Tic-Phe-Phe-OH, H-Tyr-Ticpsi[CH2-NH]Cha-Phe-OH and TIP[psi] turned out to be inverse delta agonists. TIPP analogs containing a halogen atom at the 3'-position of Tyr¹ were full or partial delta agonists. The observed dependence of agonist versus inverse agonist behavior on subtle structural modifications was not observed before and supports the two-state model of receptor activation.

In collaboration with M. Fundytus and Dr. T. Coderre at the IRCM, we conducted studies on opioid tolerance and dependence. We were able to demonstrate that TIPP[psi] greatly attenuates the development of morphine tolerance and dependence in rats. On the basis of these results it was expected that mixed mu agonist/delta antagonists may have potential as analgesics with low propensity to produce tolerance and dependence. The tetrapeptide amides H-Tyr-Tic-Phe-Phe-NH2 (TIPP-NH2) and H-Dmt-Ticpsi[CH2-NH]Phe-Phe-NH2 (DIPP-NH2[psi]) were full mu agonists in the guinea pig ileum (GPI) assay and potent delta antagonists in the mouse vas deferens (MVD) assay, thus representing the first known compounds with mixed mu agonist/delta antagonist properties. In the rat tail flick test, DIPP-NH2[psi] turned out to be a potent analgesic which upon chronic administration produced no dependence and little tolerance.

We developed a µ opioid agonist tetrapeptide, [Dmt1]DALDA, which is a potent analgesic, capable of crossing the blood-brain barrier to produce a long-lasting, centrally mediated analgesic effect when given systemically. Incorporation of this peptide together with TIPP[psi] into a bifunctional molecule resulted in the first opioid µ agonist/δ antagonist capable of producing centrally mediated analgesia upon peripheral administration and having low propensity to induce analgesic tolerance.

In collaboration with Dr. Hazel Szeto, we discovered a novel class of tetrapeptides (SS peptides), such as H-D-Arg-Dmt-Lys-Phe-NH2 (SS 31), capable of penetrating into cells, including neuronal cells, and of targeting the inner mitochondrial membrane. Because these peptides contain the artificial amino acid Dmt as antioxidant moiety, they represent the first antioxidants acting at the mitochondrial level after peripheral administration. Therefore, they have great therapeutic potential for the treatment of many diseases associated with oxidative stress, including Parkinson's disease, ALS, Alzheimer disease, atherosclerosis, ischemia reperfusion injury, etc. An IND application for the peptide SS 31 was approved by the FDA and this peptide is now in the process of being evaluated in a phase 1 clinical trial for the indication of acute myocardial infarction.

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