Senadheera 2013

Opioid Macrocyclic Tetrapeptides as Potential Leads for Drug Development: Optimization of Larger Scale Syntheses for in vivo Pharmacological Evaluation

Sanjeewa N. Senadheera,a Jay P. McLaughlin,b and Jane V. Aldricha

a Department of Medicinal Chemistry, The University of Kansas, Lawrence, KS 66045

b Torrey Pines Institute for Molecular Studies, Port St. Lucie, FL 34987

Kappa opioid receptor (KOR) antagonists have potential application as therapeutic agents in the treatment of drug abuse and depression. The natural product macrocyclic tetrapeptide CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]) was reported to be a novel KOR antagonist with modest affinity and selectivity for KOR (Saito et al., J. Antiobiot. 2002, 55, 847-854). These compounds are potential candidates for drug development because of their low molecular weight and expected metabolic stability in vivo, but the small ring size can make their synthesis difficult, resulting in low yields and dimeric cyclic octapeptides as the major product. We are synthesizing analogs of CJ-15,208 by modifying our initial synthetic protocol (Ross et al., Tetrahedron Lett. 2010, 51, 5020-5023) to prepare larger quantities of these macrocyclic tetrapeptides for detailed pharmacological evaluation in vivo following systemic administration. Modifications and optimizations to 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. The pharmacological evaluations for selected macrocyclic tetrapeptides will also be presented. Research supported by NIDA grants R01 DA018832 and R01 DA 023924.