Synthesis and Evaluation of Melphalan-Containing N,N-Dialkylenkephalin Analogues as Irreversible Antagonists of the δ Opioid Receptor

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.