Abstract
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 “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 analogs, 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
(
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.