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

The mu-opioid agonists endomorphin-1 (Tyr-Pro-Trp-Phe-NH2) and endomorphin-2 (Tyr-Pro-Phe-Phe-NH2) exhibit an extremely high selectivity for the mu-opioid receptor and thus represent a potential framework for modi. cation 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 ( IC50 = 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 modi. cations are needed to improve its in vivo pro. le. (c) 2008 Elsevier Ltd. All rights reserved.