Heyl D L, Mosberg H I
College of Pharmacy, University of Michigan, Ann Arbor.
Int J Pept Protein Res. 1992 May;39(5):450-7. doi: 10.1111/j.1399-3011.1992.tb01449.x.
The previously described cyclic delta opioid receptor-selective tetrapeptide H-Tyr-D-Cys-Phe-D-Pen-OH (JOM-13) was modified at residue 3 by incorporation of both natural and unnatural amino acids with varying steric, electronic, and lipophilic properties. Effects on mu and delta opioid receptor binding affinities were evaluated by testing the compounds for displacement of radiolabeled receptor-selective ligands in a guinea pig brain receptor binding assay. Results obtained with the bulky aromatic 1-Nal3 and 2-Nal3 substitutions suggest that the shape of the receptor subsite with which the side chain of the internal aromatic residue interacts differs for delta and mu receptors. This subsite of either receptor can accommodate the transverse steric bulk of the 1-Nal3 side chain but only the delta receptor can readily accept the more elongated 2-Nal3 side chain. Several analogs with pi-excessive heteroaromatic side chains in residue 3 were examined. In general, these analogs display diminished binding to mu and delta receptors, consistent with previous findings for analogs with residue 3 substitutions of modified electronic character. Several analogs with alkyl side chains in residue 3 were also examined. While delta receptor binding affinity is severely diminished with Val3, Ile3, and Leu3 substitutions, Cha3 substitution is very well tolerated, indicating that, contrary to the widely held belief, an aromatic side chain in this portion of the ligand is not required for delta receptor binding. Where possible, comparison of results in this delta-selective tetrapeptide series with those reported for analogous modification in the cyclic delta-selective pentapeptide [D-Pen2, D-Pen5]enkephalin (DPDPE) and linear pentapeptide enkephalins reveals similar trends.
先前描述的环型δ阿片受体选择性四肽H-Tyr-D-Cys-Phe-D-Pen-OH（JOM-13）在第3位残基处进行了修饰，引入了具有不同空间、电子和脂溶性性质的天然和非天然氨基酸。通过在豚鼠脑受体结合试验中测试化合物对放射性标记的受体选择性配体的置换作用，评估了它们对μ和δ阿片受体结合亲和力的影响。用体积较大的芳香族1-Nal3和2-Nal3取代得到的结果表明，内部芳香族残基侧链与之相互作用的受体亚位点的形状在δ和μ受体中有所不同。任一受体的该亚位点都能容纳1-Nal3侧链的横向空间体积，但只有δ受体能轻易接受更长的2-Nal3侧链。研究了几种在第3位残基处带有富π杂芳族侧链的类似物。一般来说，这些类似物对μ和δ受体的结合能力减弱，这与先前对具有经修饰电子特性的第3位残基取代的类似物的研究结果一致。还研究了几种在第3位残基处带有烷基侧链的类似物。虽然用Val3、Ile3和Leu3取代会严重降低δ受体结合亲和力，但Cha3取代却能很好地耐受，这表明，与普遍看法相反，配体这一部分中的芳香族侧链对于δ受体结合并非必需。在可能的情况下，将该δ选择性四肽系列的结果与环型δ选择性五肽[D-Pen2, D-Pen5]脑啡肽（DPDPE）和线性五肽脑啡肽中类似修饰所报道的结果进行比较，发现了相似的趋势。
