N,N-Dialkylated leucine enkephalin analogues containing melphalan (Mel) in place of Phe4were synthesized as potentially irreversible antagonists of the δ opioid receptor. These compounds, along with the corresponding Phe4peptides, were tested for both agonist and antagonist activity in the GPI and MVD smooth muscle preparations. All but two of the eight compounds showed antagonist activity at 1 against [d-a la2,D-Leu5] enkephalin (DADLE) in the MVD when tested under reversible conditions; in all cases the Mel4peptide had lower activity against DADLE than did the corresponding Phe4peptide. At higher concentrations (10 μM) the two active Mel4analogues, (benzyl)2Tyr-Gly-Gly-Mel-Leu (2a) and (allyl)2Tyr-Aib-Aib-Mel-Leu (3a), both showed weak irreversible antagonism at the δ receptor. Compound 2a was a selective irreversible δ opioid antagonist while 3a was an irreversible antagonist at both the μ and δ opioid receptors.