Mosberg H I, Haaseth R C, Ramalingam K, Mansour A, Akil H, Woodard R W
College of Pharmacy, University of Michigan, Ann Arbor.
Int J Pept Protein Res. 1988 Jul;32(1):1-8. doi: 10.1111/j.1399-3011.1988.tb00919.x.
In order to assess the individual effects of each of the 3-methyl groups in residue 2 of [D-Pen2, D-Pen5]enkephalin on binding affinity to mu and delta opioid receptors, (2S,3S)methylcysteine ((3S)Me-D-Cys) and (2S,3R)methylcysteine ((3R)Me-D-Cys) were synthesized and incorporated into the analogs, [(3S)Me-D-Cys2, D-Pen5] enkephalin and [(3R)Me-D-Cys2, D-Pen5]enkephalin. Of these analogs, [(3S)Me-D-Cys2, D-Pen5]enkephalin appears from 1H n.m.r. spectra to assume a conformation similar to those of [D-Pen2, D-Pen5]enkephalin and the less delta receptor-selective, but more potent, [D-Cys2, D-Pen5]enkephalin. Assessment of binding affinity to mu and delta receptors revealed that [(3S)Me-D-Cys2, D-Pen5]enkephalin exhibits delta receptor affinity intermediate between [D-Pen2, D-Pen5]enkephalin and [D-Cys2, D-Pen5]enkephalin while its mu receptor affinity is similar to that of [D-Cys2, D-Pen5]enkephalin. These results suggest that, for [D-Pen2, D-Pen5]enkephalin, adverse steric interactions between the D-Pen2 pro-R methyl group and the mu receptor binding site lead to the low mu receptor binding affinity observed for this analog. By contrast, both the pro-R and pro-S D-Pen2 methyl groups lead to minor steric interactions which contribute to the somewhat lower delta receptor affinity of this compound.
为了评估[D-青霉胺2，D-青霉胺5]脑啡肽残基2中3个甲基各自对μ和δ阿片受体结合亲和力的单独影响，合成了(2S,3S)甲基半胱氨酸((3S)Me-D-Cys)和(2S,3R)甲基半胱氨酸((3R)Me-D-Cys)，并将其掺入类似物[(3S)Me-D-Cys2，D-青霉胺5]脑啡肽和[(3R)Me-D-Cys2，D-青霉胺5]脑啡肽中。在这些类似物中，[(3S)Me-D-Cys2，D-青霉胺5]脑啡肽的1H核磁共振谱显示其构象与[D-青霉胺2，D-青霉胺5]脑啡肽以及δ受体选择性较低但活性更强的[D-半胱氨酸2，D-青霉胺5]脑啡肽相似。对μ和δ受体结合亲和力的评估表明，[(3S)Me-D-Cys2，D-青霉胺5]脑啡肽的δ受体亲和力介于[D-青霉胺2，D-青霉胺5]脑啡肽和[D-半胱氨酸2，D-青霉胺5]脑啡肽之间，而其μ受体亲和力与[D-半胱氨酸2，D-青霉胺5]脑啡肽相似。这些结果表明，对于[D-青霉胺2，D-青霉胺5]脑啡肽，D-青霉胺2的前R甲基与μ受体结合位点之间不利的空间相互作用导致该类似物的μ受体结合亲和力较低。相比之下，前R和前S D-青霉胺2甲基均导致较小的空间相互作用，这导致该化合物的δ受体亲和力略低。
