Heyl D L, Schmitter S J, Bouzit H, Johnson T W, Hepp A M, Kurtz K R, Mousigian C
Department of Chemistry, Eastern Michigan University, Ypsilanti.
Int J Pept Protein Res. 1994 Nov;44(5):420-6. doi: 10.1111/j.1399-3011.1994.tb00177.x.
Deltorphins I and II (Tyr-D-Ala-Phe-Asp-Val-Val-Gly NH2 and Tyr-D-Ala-Phe-Glu-Val-Val-Gly NH2) display a high degree of delta-opioid receptor selectivity. Since they lack the intervening Gly3 residue found between the Tyr and Phe aromatic moieties in pentapeptide enkephalins, deltorphins I and II resemble a previously described series of cyclic tetrapeptides based on Tyr-c[D-Cys-Phe-D-Pen] (JOM-13). With the goal of development of structure-activity relationships for deltorphins and comparison with that of the cyclic tetrapeptides, ten analogs of deltorphin I were synthesized in which Phe3 was replaced with specific aromatic and nonaromatic amino acids with varying physicochemical properties. Results indicated that analogs containing the bicyclic aromatic amino acids 3-(1-naphthyl)-L-alanine [1-Nal; Ki(mu) = 767 nM, Ki(delta) = 7.70 nM], 3-(2-naphthyl)-L-alanine [2-Nal; Ki(mu) = 1910 nM, Ki(delta) = 49.2 nM], tryptophan [Ki(mu) = 1250 nM, Ki(delta) = 23.9 nM], and 3-(3-benzothienyl)-L-alanine [Bth; Ki(mu) = 112 nM, Ki(delta) = 3.36 nM] were fairly well tolerated at mu- and delta-receptors, though affinity was compromised to varying degrees relative to deltorphin I. Shortening the Phe side chain by incorporation of phenylglycine (Pgl) was detrimental to both mu (Ki = 4710 nM) and delta (Ki = 15.6 nM) binding, while extension of the side chain with homophenylalanine (Hfe) enhanced mu binding (Ki = 67.8 nM), leaving delta affinity unaffected (Ki = 2.64 nM). Substitution with nonaromatic amino acids valine and isoleucine led expectedly to poor opioid binding [Ki(mu) = > or = 10,000 nM for each, Ki(delta) = 160 and 94.7 nM, respectively], while peptides containing cyclohexylalanine (Cha) and leucine surprisingly retained affinity at both mu (Ki = 322 and 1240 nM, respectively) and delta (Ki = 10.5 and 12.4 nM, respectively) sites. In general, these trends mirror those observed for similar modification in Tyr-c[D-Cys-Phe-D-Pen].
强啡肽 I 和 II（酪氨酸 - D - 丙氨酸 - 苯丙氨酸 - 天冬氨酸 - 缬氨酸 - 缬氨酸 - 甘氨酸 NH₂ 和酪氨酸 - D - 丙氨酸 - 苯丙氨酸 - 谷氨酸 - 缬氨酸 - 缬氨酸 - 甘氨酸 NH₂）表现出高度的 δ - 阿片受体选择性。由于它们在五肽脑啡肽的酪氨酸和苯丙氨酸芳香基团之间缺少中间的甘氨酸³残基，强啡肽 I 和 II 类似于先前描述的基于酪氨酸 - c[D - 半胱氨酸 - 苯丙氨酸 - D - 青霉胺]的一系列环四肽（JOM - 13）。为了建立强啡肽的构效关系并与环四肽进行比较，合成了强啡肽 I 的十种类似物，其中苯丙氨酸³被具有不同物理化学性质的特定芳香族和非芳香族氨基酸取代。结果表明，含有双环芳香族氨基酸 3 - (1 - 萘基) - L - 丙氨酸 [1 - Nal；Ki(μ) = 767 nM，Ki(δ) = 7.70 nM]、3 - (2 - 萘基) - L - 丙氨酸 [2 - Nal；Ki(μ) = 1910 nM，Ki(δ) = 49.2 nM]、色氨酸 [Ki(μ) = 1250 nM，Ki(δ) = 23.9 nM] 和 3 - (3 - 苯并噻吩基) - L - 丙氨酸 [Bth；Ki(μ) = 112 nM，Ki(δ) = 3.36 nM] 的类似物在 μ 和 δ 受体上的耐受性相当好，尽管相对于强啡肽 I，亲和力在不同程度上受到了影响。通过引入苯甘氨酸（Pgl）缩短苯丙氨酸侧链对 μ（Ki = 4710 nM）和 δ（Ki = 15.6 nM）结合均不利，而用高苯丙氨酸（Hfe）延长侧链增强了 μ 结合（Ki = 67.8 nM），δ 亲和力未受影响（Ki = 2.64 nM）。用非芳香族氨基酸缬氨酸和异亮氨酸取代预期会导致较差的阿片样物质结合 [每种的 Ki(μ) = ≥10,000 nM，Ki(δ) 分别为 160 和 94.7 nM]，而含有环己基丙氨酸（Cha）和亮氨酸的肽令人惊讶地在 μ（Ki 分别为 322 和 1240 nM）和 δ（Ki 分别为 10.5 和 12.4 nM）位点都保留了亲和力。总体而言，这些趋势与在酪氨酸 - c[D - 半胱氨酸 - 苯丙氨酸 - D - 青霉胺]中观察到的类似修饰趋势一致。
