Liebmann C, Schnittler M, Hartrodt B, Born I, Neubert K
Biologische Fakultät, Institut für Biochemie und Biophysik, Friedrich-Schiller-Universitat Jena.
Pharmazie. 1991 May;46(5):345-8.
The beta -casomorphin-5 sequence was systematically modified by substitution of the naturally occurring amino acids. The derivatives are compared on the basis of their affinities towards mu 1-, mu 2 and delta -opioid binding sites estimated by means of binding studies with [3H]dihydromorphine and [3H]D-Ala2-Leu5-enkephalin as labels and computer curve fitting. A C-terminal amide group which is known to increase mu-site affinity of beta -CM-4 and beta -CM-5 mainly enhances the mu 2-site affinity. Furthermore, the Pro4-amide structure, which seems to be responsible for the affinity enhancement can be substituted by the pyrrolidide ring structure. Modifications in position 2, 3 and 4 can lead to an increase in mu 1-, mu 2- or delta -site affinity and/or selectivity. The specificity of these effects might be dependent on the respective changes in the charge or hydrophobicity due to the introduction of other amino acids. The results suggest firstly that the alternating proline residues in the beta -CM-5 molecule are not absolutely necessary for its mu-site affinities, and secondly that both opioid receptor subtype affinity and selectivity may be modified by changing charge and/or hydrophobicity in the middle part of the beta -casomorphin molecule.
通过天然存在的氨基酸的取代，对β-酪蛋白吗啡-5序列进行了系统修饰。利用[3H]二氢吗啡和[3H]D-Ala2-Leu5-脑啡肽作为标记进行结合研究，并通过计算机曲线拟合估计衍生物对μ1-、μ2和δ-阿片样物质结合位点的亲和力，从而对这些衍生物进行比较。已知能增加β-CM-4和β-CM-5的μ位点亲和力的C末端酰胺基团主要增强μ2位点的亲和力。此外，似乎负责亲和力增强的Pro4-酰胺结构可被吡咯烷环结构取代。2、3和4位的修饰可导致μ1-、μ2-或δ位点亲和力和/或选择性增加。这些效应的特异性可能取决于由于引入其他氨基酸而导致的电荷或疏水性的相应变化。结果表明，首先，β-CM-5分子中交替的脯氨酸残基对其μ位点亲和力不是绝对必要的；其次，通过改变β-酪蛋白吗啡分子中部的电荷和/或疏水性，可以改变阿片受体亚型的亲和力和选择性。
