[Nα-BenzylTyr1,cyclo(D-Asp5,Dap8)]dynorphin A-(1-11)NH2 cyclized in the address domain is a novel K-opioid receptor antagonist

The cyclic dynorphin A analogue [N-alpha-benzylTyr(1), cyclo(D-Asp(5),Dap(8))]dynorphm A-(1-11)NH2 (Dap = 2,3-diaminopropionic acid) exhibits nanomolar affinity (30 nM) and high selectivity (K-i ratio (kappa/u delta) = 1/194/330) for kappa-opioid receptors. This analogue antagonizes dynorphin A-(1-13)NH2 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.