Optimized and Improved Larger Scale Synthesis of Opioid Macrocyclic Tetrapeptides with Potential for Drug Development
Sanjeewa N. Senadheera,a Shainnel O. Eans,b Jay P. McLaughlin,b Jane V. Aldricha
a Department of Medicinal Chemistry, The University of Kansas, Lawrence, KS 66045, USA b Torrey Pines Institute for Molecular Studies, Port St. Lucie, FL 34987, USA
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 have demonstrated potential as therapeutic agents in the treatment of various diseases including drug abuse and pain. The natural product macrocyclic tetrapeptide KOR ligand CJ-15,208 (Figure 1, Saito et al., J. Antiobiot. 2002, 55, 847) can prevent reinstatement of cocaine seeking behavior in vivo following oral administration (Aldrich et al., J. Nat. Prod. 2013, 76, 433). These macrocyclic peptides are potential candidates for drug development because of their low molecular weight and expected metabolic stability in vivo, but the small 12-membered ring size can make their synthesis difficult, resulting in low yields and dimeric macrocyclic octapeptides as the major products. We are synthesizing analogs of CJ-15, 208 by modifying our initial synthetic protocol (Ross et al., Tetrahedron Lett. 2010, 51, 5020) to prepare larger quantities of these macrocyclic tetrapeptides for detailed pharmacological evaluation in vivo following systemic administration. The macrocyclic tetrapeptides were synthesized by a combination of solid phase synthesis of the linear peptide precursors, followed by cyclization in solution. Optimization of the crucial cyclization step and the use of normal- phase column chromatography increased the yields of the final products, providing sufficient material for extensive characterization in vivo. Pharmacological results for selected macrocyclic tetrapeptides will also be presented. These novel macrocyclic tetrapeptides are promising candidates for the development of potential peptide KOR therapeutic ligands. Research supported by NIDA grants R01 DA018832 and R01 DA 023924.