Ligands for kappa opioid receptors (KOR) have potential therapeutic application in a number of areas, including in the treatment of pain and drug abuse. A major challenge in developing peptides for these receptors and other targets as potential therapeutic agents has been their metabolic stability and distribution following systemic administration. The novel cyclic tetrapeptide CJ-15,208 was reported to be a KOR antagonist in vitro (Saito et al., J. Antibiot. 2002, 55, 847). Because of its cyclic structure this peptide was expected to be resistant to proteolytic degradation and potentially systemically active. Therefore we synthesized this peptide (Ross et al., Tetrahedron Lett. 2010, 51, 5020) along with a number of analogs and evaluated selected peptides in vivo. Unexpectedly the lead peptide exhibited analgesic activity in the 55oC warm water tail withdrawal assay in mice following systemic (intraperitoneal) administration (ED50 (and 95% confidence interval) = 4.5 (1.2-20.3) mg/kg). Characterization in additional in vivo assays indicated that this peptide is a mixed agonist/antagonist and suggests that it could be a potentially clinically useful analgesic with decreased liabilities compared to current narcotic analgesics (e.g. morphine). Analogs of the lead peptide exhibited different pharmacological profiles in vivo in terms of agonist activity and the opioid receptors involved. An analog that exhibits primarily KOR antagonist activity in vivo is also systemically active and blocks stress-induced reinstatement of cocaine seeking behavior. These cyclic peptides represent significant advances in the development of potential peptide therapeutics for KOR. Research supported by NIDA grants R01 DA018832 and DA023924.

Novel kappa opioid peptides with drug-like properties

242nd National Meeting (2011)

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