Effect of aromatic amino acid substitutions in the 3-position of cyclic beta-casomorphin analogues on mu-opioid agonist/delta-opioid antagonist properties.

R Schmidt, B C Wilkes, N N Chung, C Lemieux, P W Schiller
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Abstract

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.

环-卡啡啡类似物3位芳香族氨基酸取代对阿片激动剂/阿片拮抗剂性能的影响。
β -casomorphin-5类似物H-Tyr-c[- d - orn -2-Nal- d - pro - gly -] (2-Nal = 2-萘基丙氨酸)是第一个报道的具有混合激动剂/拮抗剂特性的环阿片肽[R]。Schmidt et al. (1994) [j].医学化学杂志,37,1136-1144]。该肽中的2-Nal3残基被苯并噻吩丙氨酸(Bta)(3)、His(Bzl)(4)、Tyr(Bzl)(5)、4′-苯并苯基苯丙氨酸(Bpa)(6)、4′-苯并苯基苯丙氨酸(Bzp)(7)、甲状腺原氨酸(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,并通过mu和delta受体代表结合实验和生物实验测定了所得化合物的体外阿片活性谱。类似物3、12和14在受体代表豚鼠回肠(GPI)实验中是完全激动剂,在受体代表小鼠输精管(MVD)实验中也是激动剂。在MVD实验中,后一种化合物的激动剂作用被高选择性的δ受体拮抗剂h - tyri - tic - phei - pheoh (TIPP)所拮抗,表明它们是由δ受体激活触发的。在GPI实验中,含有Bzp3-和Bip3-的肽7和10被证明是mu选择性激动剂h - tyr - d - ala - ph - ph - nh2的拮抗剂。其他类似物是弱的部分激动剂,与亲本肽1相比,表现出明显降低的mu受体亲和力。化合物4-10在MVD试验中被发现是delta拮抗剂。类似物4和9表现出与亲本肽1相似的δ拮抗剂效力,而化合物5-8和10对DPDPE和deltorphin I表现出3-12倍的δ拮抗剂效力,并且在大多数情况下增加了δ受体亲和力。这些结果表明,δ受体可以耐受具有δ激动剂或δ拮抗剂性质的环β -casomorphin类似物中3位的大块芳香侧链。然而,这些化合物在几乎所有情况下都显示出明显降低的mu受体亲和力。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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