1. Academic Validation
  2. Novel highly potent mu-opioid receptor antagonist based on endomorphin-2 structure

Novel highly potent mu-opioid receptor antagonist based on endomorphin-2 structure

  • Bioorg Med Chem Lett. 2008 Feb 15;18(4):1350-3. doi: 10.1016/j.bmcl.2008.01.009.
Jakub Fichna 1 Jean-Claude do-Rego Tomasz Janecki Renata Staniszewska Jeroen Poels Jozef Vanden Broeck Jean Costentin Peter W Schiller Anna Janecka
Affiliations

Affiliation

  • 1 Laboratory of Biomolecular Chemistry, Institute of Biomedicinal Chemistry, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, PL, Poland.
Abstract

The mu-opioid agonists endomorphin-1 (Tyr-Pro-Trp-Phe-NH(2)) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH(2)) exhibit an extremely high selectivity for the mu-opioid receptor and thus represent a potential framework for modification into mu-antagonists. Here we report on the synthesis and biological evaluation of novel [d-2-Nal(4)]endomorphin-2 analogs, [Sar(2),d-2-Nal(4)]endomorphin-2 and [Dmt(1),Sar(2),d-2-Nal(4)]endomorphin-2 (Dmt=2'6'-dimethyltyrosine; Sar=N-methylglycine, sarcosine; d-2-Nal=3-(2-naphthyl)-d-alanine). [Dmt(1),Sar(2),d-2-Nal(4)]endomorphin-2 possessed very high affinity for the mu-opioid receptor (IC(50)=0.01+/-0.001 nM) and turned out to be a potent and extremely selective mu-opioid receptor antagonist, as judged by the in vitro aequorin luminescence-based calcium assay (pA(2)=9.19). However, in the in vivo hot plate test in mice this analog was less potent than our earlier mu-opioid receptor antagonist, [Dmt(1),d-2-Nal(4)]endomorphin-2 (antanal-2). The exceptional mu-opioid receptor in vitro activity and selectivity of [Dmt(1), Sar(2),d-2-Nal(4)]endomorphin-2 makes this analog a valuable pharmacological tool, but further modifications are needed to improve its in vivo profile.

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