Lazarus L H, Salvadori S, Santagada V, Tomatis R, Wilson W E
Peptide Neurochemistry Section, National Institute of Environmental Health Sciences, Research Triangle Park, North Carolina 27709.
J Med Chem. 1991 Apr;34(4):1350-5. doi: 10.1021/jm00108a017.
Deltorphins A, B, and C exhibit high delta-affinities (Ki = 0.12-0.31 nM) and very high delta-receptor binding selectivities (Ki mu/Ki delta = 1800-4100). A study of the delta-receptor binding properties of 15 deltorphin analogues focused primarily on the influence of the anionic group in the C-terminal tetrapeptide. Amidation of the beta-carboxyl groups of [Asp7], [Glu4], or [Asp4] in deltorphins A, B, and C, respectively, yielded peptides with enhanced mu-receptor affinities and minor changes in delta-affinities (Ki delta = 0.20-0.65 nM), but 5-8-fold diminished delta-selectivities. A free C-terminal carboxyl group markedly reduced delta-affinities and decreased delta-selectivities 6-11-fold; thus, the C-terminal amide group critically facilitates delta-affinity. Modifications in the anionic charged group or hydrophobic residues in the C-terminal tetrapeptide address domain of deltorphin A altered spatial distributions critical for delta-affinity and selectivity; e.g., [Nle6]deltorphin A enhanced mu-affinity and lowered delta-selectivity by two-thirds; the progressive, step-wise repositioning of Asp in deltorphin C (from position 4 to 7) was accompanied by linear decreases in delta-affinities and -selectivities, and increased mu-affinities of these peptides; enhancement of the charge density to -2, in [Asp6, Asp-OH7]deltorphin A, decreased delta-affinity and -selectivity, while [Asp4,5,His7]deltorphin A bound to neither mu- nor delta-sites. These results demonstrate that while an anionic group may occasionally facilitate high delta-receptor affinity, it represents an absolute requirement for the high delta-binding selectivity of these peptides. The locations of the charged groups relative to hydrophobic residues in the address domain of the peptide are also critical determinants for both delta-affinity and -selectivity.
德尔托啡肽A、B和C表现出高δ亲和力（Ki = 0.12 - 0.31 nM）和非常高的δ受体结合选择性（Kiμ/Kiδ = 1800 - 4100）。一项对15种德尔托啡肽类似物的δ受体结合特性的研究主要集中在C端四肽中阴离子基团的影响上。分别对德尔托啡肽A、B和C中的[Asp7]、[Glu4]或[Asp4]的β-羧基进行酰胺化，得到的肽具有增强的μ受体亲和力，且δ亲和力有微小变化（Kiδ = 0.20 - 0.65 nM），但δ选择性降低了5 - 8倍。游离的C端羧基显著降低了δ亲和力，并使δ选择性降低了6 - 11倍；因此，C端酰胺基团对δ亲和力起着关键的促进作用。对德尔托啡肽A的C端四肽识别域中的阴离子电荷基团或疏水残基进行修饰，改变了对δ亲和力和选择性至关重要的空间分布；例如，[Nle6]德尔托啡肽A增强了μ亲和力，并使δ选择性降低了三分之二；德尔托啡肽C中Asp（从第4位到第7位）的逐步、逐位重新定位伴随着这些肽的δ亲和力和选择性呈线性下降，以及μ亲和力增加；[Asp6, Asp - OH7]德尔托啡肽A中电荷密度增加到 - 2，降低了δ亲和力和选择性，而[Asp4,5,His7]德尔托啡肽A既不与μ位点也不与δ位点结合。这些结果表明，虽然阴离子基团偶尔可能有助于高δ受体亲和力，但它是这些肽具有高δ结合选择性的绝对必要条件。肽识别域中带电基团相对于疏水残基的位置也是δ亲和力和选择性的关键决定因素。
