Schmidt R, Wilkes B C, Chung N N, Lemieux C, Schiller P W
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Quebec, Canada.
Int J Pept Protein Res. 1996 Nov;48(5):411-9.
The beta-casomorphin-5 analog H-Tyr-c[-D-Orn-2-Nal-D-Pro-Gly-] (2-Nal = 2-naphthylalanine) was the first reported cyclic opioid peptide with mixed mu agonist/delta antagonist properties [R. Schmidt et al. (1994) J. Med. Chem. 37, 1136-1144]. The 2-Nal3 residue in this peptide was replaced with benzothienylalanine (Bta) (3), His(Bzl) (4), Tyr(Bzl) (5), 4'-benzoylphenylalanine (Bpa) (6), 4'-benzylphenylalanine (Bzp) (7), thyronine (Thy) (8), thyroxine (Thx) (9), 4'-biphenylalanine (Bip) (10), 4'-biphenylglycine (Bpg) (12) and 3,3-diphenylalanine (Dip) (14), and the in vitro opioid activity profiles of the resulting compounds were determined in mu and delta receptor-representative binding assays and bioassays. Analogues 3, 12 and 14 were full agonists in the mu receptor-representative guinea-pig ileum (GPI) assay and also were agonists in the delta receptor-representative mouse vas deferens (MVD) assay. The agonist effects of the latter compounds in the MVD assay were antagonized by the highly selective delta antagonist H-Tyr-Tic-Phe-Phe-OH (TIPP), indicating that they were triggered by delta receptor activation. The Bzp3- and Bip3- containing peptides 7 and 10 turned out to be mu antagonists against the mu selective agonist H-Tyr-D-Ala-Phe-Phe-NH2 in the GPI assay. The other analogues were weak partial mu agonists which displayed remarkably decreased mu receptor affinity as compared to parent peptide 1. Compounds 4-10 were found to be delta antagonists in the MVD assay. Analogues 4 and 9 exhibited delta antagonist potency similar to that of parent peptide 1, while compounds 5-8 and 10 showed 3-12-fold higher delta antagonist potency against DPDPE and deltorphin I and, in most cases, increased delta receptor affinity. These results indicate that the delta receptor tolerates bulky aromatic side chains in the 3-position of cyclic beta-casomorphin analogs with either delta agonist or delta antagonist properties. However, these compounds displayed drastically reduced mu receptor affinity in nearly all cases.
β-酪蛋白吗啡-5类似物H-Tyr-c[-D-Orn-2-Nal-D-Pro-Gly-]（2-Nal = 2-萘基丙氨酸）是首个被报道的具有μ激动剂/δ拮抗剂混合特性的环阿片肽[R. Schmidt等人（1994年），《药物化学杂志》37卷，1136 - 1144页]。该肽中的2-Nal3残基被苯并噻吩基丙氨酸（Bta）（3）、His(Bzl)（4）、Tyr(Bzl)（5）、4'-苯甲酰基苯丙氨酸（Bpa）（6）、4'-苄基苯丙氨酸（Bzp）（7）、甲状腺素（Thy）（8）、甲状腺素（Thx）（9）、4'-联苯丙氨酸（Bip）（10）、4'-联苯甘氨酸（Bpg）（12）和3,3-二苯丙氨酸（Dip）（14）取代，并在μ和δ受体代表性结合试验及生物试验中测定了所得化合物的体外阿片样物质活性谱。类似物3、12和14在μ受体代表性豚鼠回肠（GPI）试验中是完全激动剂，在δ受体代表性小鼠输精管（MVD）试验中也是激动剂。后一种化合物在MVD试验中的激动作用被高选择性δ拮抗剂H-Tyr-Tic-Phe-Phe-OH（TIPP）拮抗，表明它们是由δ受体激活触发的。含Bzp3和Bip3的肽7和10在GPI试验中对μ选择性激动剂H-Tyr-D-Ala-Phe-Phe-NH2是μ拮抗剂。其他类似物是弱部分μ激动剂，与母体肽1相比，它们的μ受体亲和力显著降低。在MVD试验中发现化合物4 - 10是δ拮抗剂。类似物4和9表现出与母体肽1相似的δ拮抗剂效力，而化合物5 - 8和10对DPDPE和强啡肽I的δ拮抗剂效力高3 - 12倍，并且在大多数情况下，δ受体亲和力增加。这些结果表明，δ受体能够耐受具有δ激动剂或δ拮抗剂特性的环β-酪蛋白吗啡类似物3位上的庞大芳香侧链。然而，这些化合物在几乎所有情况下都表现出显著降低的μ受体亲和力。
