Snyder K R, Story S C, Heidt M E, Murray T F, DeLander G E, Aldrich J V
College of Pharmacy, Oregon State University, Corvallis 97331.
J Med Chem. 1992 Nov 13;35(23):4330-3. doi: 10.1021/jm00101a010.
A series of dynorphin A-(1-13) amide (Dyn A-(1-13)NH2) analogues containing lysine or N epsilon-acetyllysine (Lys(Ac)) was prepared by solid-phase peptide synthesis and evaluated for opioid receptor affinity in radioligand binding assays and for opioid activity in the guinea pig ileum (GPI). Substitutions were made at positions 6, 7, 9, 11, and 13, the basic amino acids in the C-terminus of the peptide, in order to assess the individual contributions of these residues to the kappa opioid receptor affinity and selectivity of Dyn A-(1-13)NH2. While substitutions of Lys(Ac) for Arg in position 6 did not affect kappa receptor affinity, it enhanced affinity for mu and delta receptors and therefore caused a loss of kappa receptor selectivity. When Lys(Ac) was substituted for Arg9, kappa opioid receptor affinity was enhanced and kappa receptor selectivity was retained. Replacement for Arg7, Lys11, or Lys13 by Lys(Ac) resulted in both decreased affinity and selectivity for kappa receptors. These results demonstrate the importance of Arg6 to the receptor selectivity profile of Dyn A-(1-13)NH2 and indicate that, of the five basic residues in the C-terminus, only Arg9 can be replaced by a nonbasic residue without substantial loss of kappa opioid receptor selectivity.
通过固相肽合成制备了一系列含有赖氨酸或Nε-乙酰赖氨酸（Lys(Ac)）的强啡肽A-(1-13)酰胺（Dyn A-(1-13)NH2）类似物，并在放射性配体结合试验中评估其对阿片受体的亲和力，在豚鼠回肠（GPI）中评估其阿片活性。在肽C末端的碱性氨基酸位置6、7、9、11和13进行取代，以评估这些残基对Dyn A-(1-13)NH2的κ阿片受体亲和力和选择性的各自贡献。虽然在位置6用Lys(Ac)取代精氨酸不影响κ受体亲和力，但它增强了对μ和δ受体的亲和力，因此导致κ受体选择性丧失。当用Lys(Ac)取代精氨酸9时，κ阿片受体亲和力增强且κ受体选择性得以保留。用Lys(Ac)取代精氨酸7、赖氨酸11或赖氨酸13导致对κ受体的亲和力和选择性均降低。这些结果证明了精氨酸6对Dyn A-(1-13)NH2受体选择性谱的重要性，并表明，在C末端的五个碱性残基中，只有精氨酸9可以被非碱性残基取代而不会大幅丧失κ阿片受体选择性。
