Katarzyna Gach-Janczak, Anna Janeck
May 8, 2019
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Postępy Polskiej Medycyny i Farmacji
Abstract
Morphiceptin (Tyr-Pro-Phe-Pro-NH2) – an opioid peptide, originating from enzymatic degradation of milk protein, β-casein, is a selective ligand μ-opioid receptors. These receptors play a an important role in reduction of pain sensitivity and in the regulation of the functions of many systems, including the gastrointestinal tract. Due to the rapid degradation by proteolytic enzymes and low bioavailability, morphiceptin can not be used as a medicine. The aim of the project was the synthesis and evaluation of the pharmacological profile of novel morphiceptin analogs, in search of compounds with a strong analgesic and anti-diarrheal activity, which acted only peripherally and are active after oral administration. We synthesized five series of morphiceptin analogs. The most interesting turned out compounds modified with the use of β-amino acids. Modification of morphiceptin at positions 2 or 3 by introduction of β2- or β3-amino acids and additionally in position 1 by replacing Tyr by Dmt (2’,6’-dimethyltyrosine), resulted in obtaining enzymatically stable analogs with mixed opioid receptor affinity profiles. An analog of the sequence Dmt-D-Ala-(R)-β2-1-Nal-Pro-NH2in vivo experiments in mice. This peptide showed a strong antinociceptive effect (peripheral analgesic) and antidiarrheal activity (comparable to loperamide) after intraperitoneal as well as oral administration. The PAMPA test, showed that this compound did not cross the artificial membrane imitating the blood-brain barrier and therefore its action should be only peripheral. The new analog may become an interesting lead compound in the development of peripherally restricted drugs for the treatment of gastrointestinal disorders.