Journal
BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
Volume 106, Issue 2, Pages 106-113Publisher
WILEY
DOI: 10.1111/j.1742-7843.2009.00476.x
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Funding
- Polish Ministry of Science [125/N-POLONIUM/2008/0, NN 401 0064 35]
- Medical University of Lodz [503-1099-1]
- Polpharma Foundation For Development of Polish Pharmacy and Medicine
- Bilateral Scientific Cooperation between Flanders and Poland [BIL03/18]
- Centre National de la Recherche Scientifique (CNRS, France)
- University of Calgary Research Grant Committee (URGC)
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A series of endomorphin-1 (EM-1) and endomorphin-2 (EM-2) analogues, containing non-cyclic amino acids (Ala, d-Ala, beta-Ala, NMeAla, d-NMeAla or Sar) instead of Pro in position 2 was synthesized, where NMeAla = N-methylalanine and Sar = N-methylglycine, sarcosine. The opioid activity profiles of these peptides were determined in mu and delta opioid receptor (MOR and DOR)-representative binding assays and bioassays in vitro, as well as in the mouse hot-plate test in vivo. Finally, the degradation rates of all analogues in the presence of either rat brain homogenate or selected proteolytic enzymes were determined. Analogues of EM-2 were generally more potent than the respective analogues of EM-1. EM-2 analogues with d-Ala or d-NMeAla were about twofold more potent than the parent peptide and were least prone to degradation by brain homogenate, dipeptydyl peptidase IV and aminopeptidase M. In the in vivo test, [d-Ala2]EM-2 and [d-NMeAla2]EM-2 showed much higher analgesic potency than EM-2 which confirmed the usefulness of structural modifications in obtaining new leads for pain-relief therapeutics.
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