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UF Health University of Florida
Department of Medicinal Chemistry College of Pharmacy
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Macrocyclic Tetrapeptides

CJ-15,208 prevents cocaine-seeking behavior in response to stress and to exposure to cocaine. (From Aldrich et al., J. Nat. Prod. 2013, 76, 433-438.)

The macrocyclic tetrapeptide natural product CJ-15,208 was reported to be a KOR antagonist in vitro (Saito et al., J. Antibiot. 2002, 55, 847-854). Because of its macrocyclic structure we expected this peptide would be active after systemic administration in vivo. Therefore, we undertook SAR studies of this novel opioid peptide.

When the natural product was originally isolated and characterized the stereochemistry of the tryptophan residue wasn’t determined. Therefore, we synthesized both possible isomers and found that both peptides bound to KOR with similar affinity. However, in vivo they exhibit different opioid activity profiles. Unexpectedly the natural product containing L-Trp exhibits antinociception, with KOR antagonism evident after dissipation of the agonist activity. Both isomers are completely stable to proteases, are active after oral administration and can cross the blood-brain barrier to reach opioid receptors in the brain.

Both of these peptides are promising lead compounds for the potential development of treatments for substance abuse and pain, including chronic pain. Both KOR agonists and antagonists have potential application in treating substance abuse, especially to prevent relapse in abstinent individuals. To date we have prepared >100 analogs and are examining their pharmacological activity in vitro and in vivo, along with their pharmacokinetic properties. Many of the analogs exhibit complex pharmacology involving multiple opioid receptors. In collaboration with Dr. Jay McLaughlin in the Department of Pharmacodynamics we are evaluating the SAR for antinociception and prevention of drug seeking behavior. As part of these studies we have identified a new peptide that exhibits exceptionally potent KOR antagonist activity (at 1 pmol after intracerebroventricular injection) that will serve as a new lead peptide for further structural modification.

Most of the analogs exhibit mixed agonist and antagonist activity involving more than one opioid receptor. Such multifunctional activity profiles could minimize side effects associated with mu and kappa opioid receptor selective ligands. Therefore, we are also assessing whether these peptides will exhibit reduced side effects compared to currently used opioids.

Publications

  1. J.V. Aldrich, S.N. Senadheera, N.C. Ross, M.L. Ganno, S.O. Eans, J.P. McLaughlin. The macrocyclic peptide natural product CJ-15,208 is orally active and prevents reinstatement of extinguished cocaine-seeking behavior. J. Nat Prod. 2013, 76, 433-438. https://www.ncbi.nlm.nih.gov/pubmed/23327691
  2. S.O. Eans, M.L. Ganno, K.J. Reilley, K.A. Patkar, S.N. Senadheera, J.V. Aldrich, J.P McLaughlin. The macrocyclic tetrapeptide [D-Trp]CJ-15,208 produces short-acting κ opioid receptor antagonism in the CNS after oral administration. Br. J. Pharmacol. 2013, 169, 426-436. https://www.ncbi.nlm.nih.gov/pubmed/23425081
  3. N.C. Ross, K.J. Reilley, T.F. Murray, J.V. Aldrich, J.P. McLaughlin. Novel opioid cyclic tetrapeptides: Trp isomers of CJ-15,208 exhibit distinct opioid receptor agonism and short-acting κ opioid receptor antagonism. Br. J. Pharmacol. 2012, 165, 1097-108. https://www.ncbi.nlm.nih.gov/pubmed/21671905
  4. T. Khaliq, T.D. Williams, S.N. Senadheera, J.V. Aldrich. Development of a robust, sensitive and selective liquid chromatography-tandem mass spectrometry assay for the quantification of the novel macrocyclic peptide kappa opioid receptor antagonist [D-Trp]CJ-15,208 in plasma and application to an initial pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci. 2016, 1028, 11-15. https://www.ncbi.nlm.nih.gov/pubmed/27318293
  5. J.V. Aldrich, S.N. Senadheera, N.C. Ross, K.A. Reilley, M.L. Ganno, S.E. Eans, T.F. Murray, J.P. McLaughlin. Alanine analogues of [D-Trp]CJ-15,208: novel opioid activity profiles and prevention of drug- and stress-induced reinstatement of cocaine-seeking behaviour. Br. J. Pharmacol. 2014, 171, 3212-3222. https://www.ncbi.nlm.nih.gov/pubmed/24588614
  6. J.V. Aldrich, S.S. Kulkarni, S.N. Senadheera, N.C. Ross, K.J. Reilley, S.O. Eans, M.L. Ganno, T.F. Murray, J.P. McLaughlin. Unexpected opioid activity profiles of analogues of the novel peptide kappa opioid receptor ligand CJ-15,208. ChemMedChem. 2011, 6, 1739-1745. https://www.ncbi.nlm.nih.gov/pubmed/21761566
  7. N.C. Ross, S.S. Kulkarni, J.P. McLaughlin, J.V. Aldrich. Synthesis of CJ-15,208, a novel κ-opioid receptor antagonist. Tetrahedron Lett. 2010, 51, 5020-5023. https://www.ncbi.nlm.nih.gov/pubmed/22865937