Lung F D, Collins N, Stropova D, Davis P, Yamamura H I, Porreca F, Hruby V J
Department of Chemistry, University of Arizona, Tucson, Arizona 85721, USA.
J Med Chem. 1996 Mar 1;39(5):1136-41. doi: 10.1021/jm950369c.
We previously have reported four possible binding conformation of dynorphin A (Dyn A) for the central kappa opioid receptors, induced by the address sequence, using a molecular mechanics energy minimization approach. The lowest energy conformation was found to exhibit an alpha-helical conformation in the cyclized address sequence. It was suggested that an alpha-helical conformation in the cyclized address sequence or a helical conformation induced by the conformational characteristics of the message sequence may be important for binding potency and kappa opioid receptor selectivity. Side chain to side chain lactam bridges between the i and i + 4 positions have been shown to stabilize alpha-helical conformation. Thus, a series of cyclic lactam analogues of dynorphin A(1-11)-NH2 have been designed, synthesized and evaluated by the guinea pig brain (GPB) binding assay and guinea pig ileum (GPI) bioassay to evaluate the conformational analysis prediction and, further, to investigate the conformational requirements for high potency and selectivity for kappa opioid receptors. Positions 2-6, 3-7, and 5-9 were chosen as the sites for incorporating cyclic conformational constraints. Cyclization between D-Asp(2) and Lys(6) in c[D-Asp(2),Lys(6)]Dyn A(1-11)-NH2 led to an analogue with pronounced potency and selectivity enhancement for the mu opioid receptor, whereas cyclization between D-Asp(3) and Lys(7) in c[D-Asp(3),Lys(7)]Dyn A(1-11)-NH2 led to a potent ligand (IC(50) 4.9 nM) with kappa receptor selectivity. The other analogues in the series proved to be less selective. The biological results led to the suggestion that the binding conformation for the kappa receptor may have structural requirements that are distinct from those of mu and delta receptors. Interestingly, analogues with a D-Asp at position 2, 3, or 9 were found to be more potent for the kappa receptor than analogues with an L-Asp at the same positions. It is suggested that the incorporation of D-Asp into position 2, 3, or 9 of Dyn A(1-11)-NH2 may have stereochemical and conformational effects on the nearby amino acids which can help discriminate the preference between kappa, mu, and delta receptors.
我们之前报道过，使用分子力学能量最小化方法，强啡肽A（Dyn A）由地址序列诱导产生的四种可能与中枢κ阿片受体结合的构象。发现能量最低的构象在环化的地址序列中呈现α-螺旋构象。有人提出，环化地址序列中的α-螺旋构象或由信息序列的构象特征诱导的螺旋构象对于结合亲和力和κ阿片受体选择性可能很重要。已表明i和i + 4位之间的侧链至侧链内酰胺桥可稳定α-螺旋构象。因此，设计、合成了一系列强啡肽A（1-11）-NH2的环内酰胺类似物，并通过豚鼠脑（GPB）结合试验和豚鼠回肠（GPI）生物测定进行评估，以评估构象分析预测，进而研究对κ阿片受体高效力和选择性的构象要求。选择2-6、3-7和5-9位作为引入环构象限制的位点。c[D-Asp（2），Lys（6）]Dyn A（1-11）-NH2中D-Asp（2）和Lys（6）之间的环化产生了一种对μ阿片受体具有显著效力和选择性增强的类似物，而c[D-Asp（3），Lys（7）]Dyn A（1-11）-NH2中D-Asp（3）和Lys（7）之间的环化产生了一种对κ受体具有选择性（IC（50）4.9 nM）的强效配体。该系列中的其他类似物选择性较低。生物学结果表明，κ受体的结合构象可能具有与μ和δ受体不同的结构要求。有趣的是，发现在2、3或9位带有D-Asp的类似物对κ受体的效力比在相同位置带有L-Asp的类似物更强。有人提出，在Dyn A（1-11）-NH2的2、3或9位引入D-Asp可能对附近氨基酸产生立体化学和构象影响，这有助于区分κ、μ和δ受体之间的偏好。
