Lovett J A, Portoghese P S
J Med Chem. 1987 Sep;30(9):1668-74. doi: 10.1021/jm00392a025.
N,N-Dialkylated leucine enkephalin analogues containing melphalan (Mel) in place of Phe4 were synthesized as potentially irreversible antagonists of the delta opioid receptor. These compounds, along with the corresponding Phe4 peptides, 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 microM against [D-Ala2,D-Leu5]enkephalin (DADLE) in the MVD when tested under reversible conditions; in all cases the Mel4 peptide had lower activity against DADLE than did the corresponding Phe4 peptide. At higher concentrations (10 microM) the two active Mel4 analogues, (benzyl)2Tyr-Gly-Gly-Mel-Leu (2a) and (allyl)2Tyr-Aib-Aib-Mel-Leu (3a), both showed weak irreversible antagonism at the delta receptor. Compound 2a was a selective irreversible delta opioid antagonist while 3a was an irreversible antagonist at both the mu and delta opioid receptors.
合成了用美法仑（Mel）取代苯丙氨酸4（Phe4）的N，N-二烷基化亮氨酸脑啡肽类似物，作为δ阿片受体的潜在不可逆拮抗剂。这些化合物以及相应的Phe4肽，在豚鼠回肠（GPI）和输精管（MVD）平滑肌制剂中测试了激动剂和拮抗剂活性。在可逆条件下测试时，八种化合物中除两种外，其余在1μM时对MVD中的[D-Ala2，D-Leu5]脑啡肽（DADLE）均表现出拮抗活性；在所有情况下，Mel4肽对DADLE的活性均低于相应的Phe4肽。在较高浓度（10μM）下，两种活性Mel4类似物，（苄基）2Tyr-Gly-Gly-Mel-Leu（2a）和（烯丙基）2Tyr-Aib-Aib-Mel-Leu（3a），在δ受体上均表现出弱的不可逆拮抗作用。化合物2a是一种选择性不可逆δ阿片拮抗剂，而3a是μ和δ阿片受体的不可逆拮抗剂。
