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-benzylTyr(1)]Dyn A-(1-11)NH(2) resulted in increased kappa 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-benzylTyr(1),cyclo(d-Asp(5),Dap(8))]Dyn A-(1-11)NH(2) (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.