The Effects of C-terminal Modifications on the Opioid Activity of [N-BenzylTyr1]Dynorphin A-(1-11) Analogs
Patkar, Kshitij A.
Murray, Thomas F.
Aldrich, Jane V.
American Chemicial Society
Scholarly/refereed, author accepted manuscript
This document is the Accepted Manuscript version of a Published Work that appeared in final form in the Journal of Medicinal Chemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/jm900715m.
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Structural modifications affecting the efficacy of analogs of the endogenous opioid peptide dynorphin (Dyn) A have focused on the N-terminal “message” sequence, based on the “messageaddress” concept. To test the hypothesis that changes in the C-terminal “address” domain could affect efficacy, modified amino acids and cyclic constraints were incorporated into this region of the partial agonist [N-benzylTyr1]Dyn A-(1-11). Modifications in the C-terminal domain of [NbenzylTyr1] Dyn A-(1-11)NH2 resulted in increased kappa opioid receptor (KOR) affinity for all of the linear analogs, but did not affect the efficacy of these peptides at KOR. Cyclization between positions 5 and 8 yielded [N-benzylTyr1,cyclo(D-Asp5,Dap8)]Dyn A-(1-11)NH2 (13) (Patkar et al. J. Med. Chem. 2005, 48, 4500-4503) with high selectivity for KOR. In contrast to the linear peptides, this peptide exhibits negligible efficacy in the AC assay and is a KOR antagonist. These data are consistent with our hypothesis that appropriate modifications in the “address” domain of Dyn A analogs may affect efficacy.
Patkar, K. A., Murray, T. F., & Aldrich, J. V. (2009). The Effects of C-terminal Modifications on the Opioid Activity of [N-BenzylTyr1]Dynorphin A-(1-11) Analogs. Journal of Medicinal Chemistry, 52(21), 6814–6821. http://doi.org/10.1021/jm900715m
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