A series of N,N-dialkylated leucine enkephalins were prepared in order to study the effect of substitution on antagonist activity at the δ opioid receptor. The target peptides 1–7 were evaluated in the mouse vas deferens (MVD) and guinea pig ileum (GPI) at 1 μM. All of the compounds except [N,N-di-2-phenethyl,Leu5]enkephalin (7) showed antagonist activity in the MVD against the 5 receptor agonist [d- Ala2,D-Leu5] enkephalin. The most potent congener, [N, N-dibenzyl,Leu5]enkephalin (3), was 2.5-fold more potent than (N,N-diallyl,Leu5]enkephalin (1). None of the compounds at 1 μM showed any antagonist activity against agonists for other receptor types. The N, N-di-2-phenethyl (7) and N,N-dioctyl (6) analogues showed significant agonist activity at 1 μ m in the MVD.