Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 17, Issue 11, Pages 3789-3794Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2009.04.046
Keywords
Opioid analogs; mu-Opioid receptor; Hot-plate test; Enzymatic degradation of opioids; Binding studies
Funding
- Polish Ministry of Science [125/N-POLONIUM/2008/0, NN 401 0064 35]
- Medical University of Lodz [503-1099-1]
- Centre National de la Recherche Scientific (CNRS, France)
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Endogenous mu-opioid receptor (MOR) selective peptides, endomorphin-1 (EM-1) and endomorphin-2 (EM-2), unlike so called 'typical opioids', are characterized by the presence of Pro(2) residue, which is a spacer connecting aromatic pharmacophoric residues. In order to investigate structural requirements for position 2, we synthesized endomorphin analogs incorporating, instead of Pro, unnatural amino acids with six-membered heterocyclic rings, such as piperidine 2-, 3- or 4-carboxylic acids (Pip, Nip and Inp, respectively). (R)-Nip residue turned out to be favourable for improving MOR affinity. Introduction of 2',6'-dimethyltyrosine (Dmt) instead of Tyr(1) led to obtaining [Dmt(1), (R)-Nip(2)] EM-2 which showed exceptional MOR affinity and high stability against enzymatic degradation in rat brain homogenate. In in vivo hot-plate test in mice, this analog given intracerebroventicularly (i.c.v.), produced profound supraspinal analgesia, being much more potent than EM-2. The antinociceptive effect of this analog lasted about 170 min and was almost completely reversed by beta-funaltrexamine (beta-FNA), a selective MOR antagonist. (E) 2009 Elsevier Ltd. All rights reserved.
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