[Nα-benzylTyr1,cyclo(D-Asp5,Dap 8)]-dynorphin A-(1-11)NH2 cyclized in the "address" domain is a novel κ-opioid receptor antagonist

Abstract

The cyclic dynorphin A analogue [Nα-benzylTyr1, cyclo(D-Asp5,Dap8)]dynorphin A-(1-11)NH2 (Dap = 2,3-diaminopropionic acid) exhibits nanomolar affinity (30 nM) and high selectivity (Ki ratio (κ/μ/δ) = 1/194/330) for κ-opioid receptors. This analogue antagonizes dynorphin A-(1-13)NH 2 at κ-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 κ-opioid receptor antagonist. © 2005 American Chemical Society.