As part of an effort to develop peptides with selective κ-opioid antagonist activity, a series of N-alkylated [ d-Pro 10]dynorphin A-(1-11) derivatives were made through solid-phase peptide synthesis: R-Tyr–Gly–Gly–Phe–Leu–Arg–Arg–Ile–Arg- d-Pro–LysOH, where R= N-benzyl, N-cyclopropylmethyl, N, N-dicyclopropylmethyl, or N, N-diallyl. These derivatives and dynorphin A-(1-13)NH 2 were evaluated for κ-opioid receptor binding affinity and potency as inhibitors of adenylyl cyclase. Equilibrium competition binding experiments using [ 3 H ]diprenorphine (≈600 pM) were performed on membranes prepared from cultured Chinese hamster ovary (CHO) cells stably expressing the rat κ-opioid receptor. Tissue prepared from this cell line was used to evaluate opioid peptide inhibition of forskolin-stimulated (50 μM) adenylyl cyclase activity. Displacement of [ 3 H ]diprenorphine specific binding by these peptides was observed with a rank order of affinity ( K i, nM)=[ d-Pro 10]dynorphin A-(1-11) (0.13)>dynorphin A-(1-13)NH 2 (0.34)> N-cyclopropylmethyl- (1.4)> N, N-dicyclopropylmethyl- (12.6)≈ N-benzyl- (18.3)≈ N, N-diallyl-[ d-Pro 10]dynorphin A-(1–11) (26.0). A similar rank order was observed for potency of adenylyl cyclase inhibition (IC 50, nM): [ d-Pro 10]dynorphin A-(1-11) (0.12)≈dynorphin A-(1-13)NH 2 (0.19)> N-cyclopropylmethyl- (2.7)> N, N-dicyclopropylmethyl- (13.2)≈ N, N-diallyl- (18.0)≈ N-benzyl-[ d-Pro 10]dynorphin A-(1-11) (36.4). The peptides differed in their percent maximal inhibition of adenylyl cyclase activity: dynorphin A-(1-13)NH 2 (100%)≈ N-cyclopropylmethyl- (94.3%)≈[ d-Pro 10]dynorphin A-(1-11) (87.9%)> N-benzyl- (71.4%)≫ N, N-dicyclopropylmethyl- (23.6%)≈ N, N-diallyl-[ d-Pro 10]dynorphin A-(1-11) (18.9%). As the N, N-dicyclopropylmethyl- and N, N-diallyl-[ d-Pro 10]dynorphin A-(1-11) derivatives were found to have only weak partial agonist activity with respect to adenylyl cyclase inhibition, they were evaluated for their ability to reverse dynorphin A-(1-13)NH 2 (10 nM) inhibition of adenylyl cyclase activity. N, N-dicyclopropylmethyl- and N, N-diallyl-[ d-Pro 10]dynorphin A-(1-11) reversed dynorphin A-(1-13)NH 2 inhibition to levels equal to the maximal inhibition produced by N, N-dicyclopropylmethyl- and N, N-diallyl-[ d-Pro 10]dynorphin A-(1-11) alone. This weak partial agonism combined with nanomolar potency render the N, N-dicyclopropylmethyl- and N, N-diallyl-[ d-Pro 10]dynorphin A-(1-11) compounds promising leads for further attempts to synthesize peptide κ-opioid receptor antagonists.