Narcotic analgesics such as morphine, which act primarily through mu opioid receptors (MOR), have been widely used clinically for the treatment of severe pain. However, their use is limited by severe side effects such as respiratory depression and drug dependence. Kappa opioid receptor (KOR) ligands, both agonists and antagonists, have potential as therapeutic agents in the treatment of various diseases including drug abuse and pain. The natural macrocyclic tetrapeptide CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]) was reported to be a KOR antagonist with modest affinity and selectivity for KOR (Saito et al., J. Antiobiot. 2002,  55, 847). We have demonstrated that CJ-15,208 and its analog [D-Trp]CJ-15,208 are active after oral administration (Aldrich et al., J. Nat. Prod. 2013,  76, 433; Eans et al., Br. J. Pharmacol. 2013,  in press) and therefore are excellent lead compounds for further development. One major advantage of these peptides is the limited number of possible conformations because of their macrocyclic structure. In this work we performed extensive 1D and 2D NMR spectroscopic analysis of CJ-15,208 and selected analogs, and used interproton distances measured in the 2D 1H-1H ROESY, as well as dihedral angles calculated from 3JHH, to define the secondary structural elements and backbone conformations (e.g. cis vs. trans amide bonds) of the peptides. Additionally, circular dichroism spectroscopic data provided information on turns in the backbones of these macrocyclic tetrapeptides. Linking the structural/dynamic characteristics of these ligands with their observed biological activity assists in developing pharmacophore models that will be helpful in the design of future analogs. This research was supported by NIDA grants R01 DA018832 and R01 DA023924.

Backbone conformations and hydrogen bonding patterns of analogs of the macrocyclic tetrapeptide CJ-15,208

246th National Meeting (2013)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.