The effects of C-terminal modifications on the opioid activity of [N-benzylTyr1]dynorphin A-(1-11) analogues

Kshitij A. Patkar, Thomas F. Murray, Jane V. Aldrich

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

Structural modifications affecting the efficacy of analogues of the endogenous opioid peptide dynorphin (Dyn) A have focused on the N-terminal "message" sequence based on the "message-address" 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-benzylTyr 1]Dyn A-(1-11). Modifications in the C-terminal domain of [N-benzylTyr1]Dyn A-(1-11)NH2 resulted in increased κ opioid receptor (KOR) affinity for all of the linear analogues but did not affect the efficacy of these peptides at KOR. Cyclization between positions 5 and 8 yielded [N-benzylTyr1,cyclo(D-Asp5, Dap 8)]Dyn A-(1-11)NH2 (zyklophin, 13) (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 adenylyl cyclase (AC) assay and is a KOR antagonist. These data are consistent with our hypothesis that appropriate modifications in the "address" domain of Dyn A analogues may affect efficacy.

Original languageEnglish
Pages (from-to)6814-6821
Number of pages8
JournalJournal of Medicinal Chemistry
Volume52
Issue number21
DOIs
StatePublished - Nov 12 2009

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Dynorphins
Opioid Analgesics
Peptides
Cyclic Amino Acids
Opioid Peptides
Opioid Receptors
Cyclization
Adenylyl Cyclases
dynorphin A (1-11)-amide

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

The effects of C-terminal modifications on the opioid activity of [N-benzylTyr1]dynorphin A-(1-11) analogues. / Patkar, Kshitij A.; Murray, Thomas F.; Aldrich, Jane V.

In: Journal of Medicinal Chemistry, Vol. 52, No. 21, 12.11.2009, p. 6814-6821.

Research output: Contribution to journalArticle

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