Opioid activity profiles of peptides containing overlapping portions of CJ-15,208 and CycloEM, and identification of the bioactive conformations

In 2002 Saito isolated from the fungus Ctenomyces serratus the novel KOR antagonist CJ-15,208 (1), c[Phe-pro-Phe-Trp], Ki = 29 nM. In 2009, Dolle synthesized the diastereoisomer c[Phe-pro-Phe-trp], nearly 8fold more active. These compounds exhibited no agonism in vitro, however Aldrich observed unexpected MOR agonism in vivo for 1 and derivatives. These compounds show pronounced similarity with c[Phe-Gly-Tyr-pro-trp] (2), Ki(MOR) = 34 nM synthesized by a completely different approach. The sequence Ac-trp-Phe-GlyNH2 still maintains nanomolar affinity, high MOR selectivity, and the agonist behavior. Apparently, the Trp-Phe sequence represent a pharmacoric motif for both 1 and 2.1 In this work we investigate the pharmacological profile and 3D structures of peptides containing overlapping portions of 1 and 2. This analysis led to the proposal of plausible bioactive conformations.