Nalpha-benzylTyr1,cyclo(D-Asp5,Dap8)]- dynorphin A-(1-11)NH2 cyclized in the "address" domain is a novel kappa-opioid receptor antagonist

The cyclic dynorphin A analogue [N(alpha)-benzylTyr(1),cyclo(D-Asp(5),Dap(8))]dynorphin A-(1-11)NH(2) (Dap = 2,3-diaminopropionic acid) exhibits nanomolar affinity (30 nM) and high selectivity (K(i) ratio (kappa/mu/delta) = 1/194/330) for kappa-opioid receptors. This analogue antagonizes dynorphin A-(1-13)NH(2) at kappa-opioid receptors in the adenylyl cyclase assay (K(B) = 84 nM). This is the first dynorphin A-based antagonist with modifications in the C-terminal "address" domain that alter efficacy and thus represents a novel selective kappa-opioid receptor antagonist.