We are pursuing novel macrocyclic tetrapeptides as kappa opioid receptor ligands as potential treatments for pain and addiction. Cyclic peptides are resistant to proteolytic degradation and hence can potentially display activity after systemic administration. We synthesized the natural product macrocyclic tetrapeptide, CJ-15,208 and its isomer, [D-Trp]CJ-15,208; both peptides exhibited potent <i>in vivo</i> opioid activity following oral administration to mice. Because of their promising lead-like properties, metabolism and pharmacokinetic properties of the peptides are being evaluated to facilitate their further development. These cyclic peptides are stable to proteolytic degradation, but can be oxidatively metabolized by cytochrome P450 enzymes (CYPs). In order to characterize the metabolic profile of the lead peptides, we evaluated their CYP metabolism using the most common isoforms CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Both peptides are metabolized specifically by 3A4. The details of the interactions of the compounds with CYPs will be presented.

Novel macrocyclic tetrapeptide kappa opioid receptor ligands: Cytochrome P450 metabolism and interactions

2019 Spring National Meeting

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