Kappa opioid receptor (KOR) antagonists have therapeutic potential for the treatment of drug abuse and depression. Macrocyclic tetrapeptides are promising candidates for development because of their low molecular weight, expected metabolic stability in vivo and potential oral bioavailability. The natural macrocyclic tetrapeptide CJ-15,208 was reported to be a novel KOR antagonist (Saito et al., J. Antiobiot. 2002  , 55, 847-854). The small ring size of this and related macrocyclic tetrapeptides can make their synthesis challenging. We have modified 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 to the crucial cyclization step and the use of normal-phase column chromatography increased the yields of the final products. Pharmacological results for selected macrocyclic tetrapeptides will also be presented. Research supported by NIDA grants R01 DA018832 and R01 DA23924.

Synthesis and purification of opioid macrocyclic tetrapeptides on a larger scale for in vivo pharmacological evaluation

244th National Meeting (2012)

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