Synthesis and opioid activity of conformationally constrained dynorphin A analogues .2. Conformational constraint in the ''Address'' sequence
Synthesis and opioid activity of conformationally constrained dynorphin A analogues .2. Conformational constraint in the ''Address'' sequence
复制标题
DOI：
10.1021/jm960753p
复制
发表时间：
1997-04-11
影响因子：
7.3
通讯作者：
Aldrich, JV
中科院分区：
文献类型：
--
作者：
Arttamangkul, S;Ishmael, JE;Aldrich, JV
合成了几种Dyn A-(1-13)NH2的环内酰胺类似物，以降低天然线性多肽不同区域的构象灵活性。在Amber分子模拟的基础上，设计了环[D-Asp(I)，Dap(I+3)]dyn A-(1-13)NH2(Dap=α，β-二氨基丙酸)类似物，这表明这种限制可能与α-螺旋相容。这些限制性类似物的环部分从残基3到残基9，这是Schwyzer(BioChemical 1986，25,4281)提出的在kappa受体位点采用螺旋构象的区域。还合成了在I+3位含有DAB(α，γ-二氨基丁酸)或Orn的类似物，以考察较大的环尺寸的影响。这些环肽与Kappa、Mu和Delta受体的结合亲和力和在豚鼠回肠(GPI)上的阿片活性有显著差异，Cyclo[D-Asp(6)，Dap(9)]dyn A-(1-13)NH2在GPI上表现出很高的Kappa受体亲和力和强大的激动剂活性，而Cyclo[D-Asp(3)，Dap(6)]dyn A-(1-13)NH2在所有阿片受体上表现出很弱的结合亲和力，在GPI上表现出很弱的阿片活性。环[D-Asp(5)，Dap(8)]dyn A-(1-13)NH2与kappa受体具有中等的亲和力，是本研究中kappa选择性最强的配体，但在GPI测定中表现出很弱的激动剂活性。与相应的线状多肽相比，所有环肽都表现出mU受体亲和力降低，而kappa受体亲和力保持或提高。因此，相应的线型多肽一般是u选择性的，而环限制多肽对kappa和u受体表现出轻微的选择性或非选择性。通过在6、8或9位加入DAB或Orn来增加环的大小，并没有显著影响这三种阿片受体类型的结合亲和力，也没有显著影响在GPI，环[D-Asp(I)，Dap(I+3)]衍生物在25℃和5℃时的环[D-Asp(I)，Dap(I+3)]衍生物在25℃和5℃下的环[D-Asp(I)，Dap(I+3)]衍生物的圆二色谱，表明当约束被结合在肽的N端附近时，螺旋结构的稳定性与在肽的中间处的不同。
Several cyclic lactam analogues of Dyn A-(1-13)NH2 were prepared in order to reduce the conformational flexibility in different regions of the native linear peptide. Cyclo[D-Asp(i),Dap(i+3)]Dyn A-(1-13)NH2 (Dap = alpha,beta-diaminopropionic acid) analogues were designed on the basis of molecular modeling using AMBER, which suggested that this constraint may be compatible with an alpha-helix. The cyclic portion of these constrained analogues spanned from residues 3 to 9, a region proposed by Schwyzer (Biochemistry 1986, 25, 4281) to adopt a helical conformation at kappa receptor sites. Analogues containing Dab (alpha,gamma-diaminobutyric acid) or Orn in position i + 3 were also synthesized to examine the effects of larger ring size. The cyclic peptides exhibited marked differences in binding affinities for kappa, mu, and delta receptors and in opioid activity in the guinea pig ileum (GPI); Cyclo[D-Asp(6),Dap(9)]Dyn A-(1-13)NH2 showed both high kappa receptor affinity and potent agonist activity in the GPI, while cyclo[D-Asp(3),Dap(6)]Dyn A-(1-13)NH2 exhibited very weak binding affinity at all opioid receptors as well as very weak opioid activity in the GPI. Cyclo[D-Asp(5),Dap(8)]Dyn A-(1-13)NH2 showed moderate binding affinity for kappa receptors and was the most kappa selective ligand in this study, but this peptide exhibited very weak agonist activity in the GPI assay. Compared to the corresponding linear peptides, all of the cyclic peptides exhibited decreased mu receptor affinity, while kappa receptor affinity was retained or improved. Therefore the corresponding linear peptides were generally mu selective while the cyclic constrained peptides demonstrated slight selectivity for kappa vs mu receptors or were nonselective. Increasing the ring size by incorporating Dab or Orn in positions 6, 8, or 9 did not significantly affect the binding affinity for the three opioid receptor types nor the opioid activity observed in the GPI, Circular dichroism spectra of the cyclo[D-Asp(i),Dap(i+3)] derivatives in 80% trifluoroethanol at 25 and 5 degrees C suggested differences in the stability of a helical structure when the constraint was incorporated near the N-terminus vs in the middle of the peptide.