Zyklophin ([N-benzylTyr1, cyclo(D-Asp5,Dap8)]dynorphin A-(1�11) amide) is a highly selective kappa-opioid receptor antagonist that exhibits activity in the CNS after peripheral administration (Aldrich et al., Proc. Natl. Acad. Sci. U.S.A. 2009 , 106, 18396). Utilization of this important peptide in vivo requires the synthesis and purification of the peptide on a larger scale, but structural modifications (cyclization, N-terminal modification) make its larger scale synthesis and purification more challenging. Here we describe the optimization of the solid phase synthesis, in particular the selective deprotection and cyclization of the side chains of D-Asp and Dap (2,3-diaminopropionic acid). We also utilized a modified reversed phase HPLC protocol (Chen et al., J. Chromatogr. A 2007 , 1140, 112) to substantially increase the amount of purified peptide. These modified procedures permitted preparation of the quantities of pure peptide (>100 mg) necessary for its extensive use in vivo.Research supported by NIH grants R01 DA018832 and R01 DA023924.

Optimizing a larger scale synthesis of zyklophin, a highly selective peptide kappa opioid receptor antagonist

244th National Meeting (2012)

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