Mor M, Rivara S, Silva C, Bordi F, Plazzi P V, Spadoni G, Diamantini G, Balsamini C, Tarzia G, Fraschini F, Lucini V, Nonno R, Stankov B M
Cattedra di Chemioterapia, Dipartimento di Farmacologia, Università degli Studi di Milano, via Vanvitelli 32, I-20129 Milano, Italy.
J Med Chem. 1998 Sep 24;41(20):3831-44. doi: 10.1021/jm9810093.
The CoMFA methodology was applied to melatonin receptor ligands in order to establish quantitative structure-affinity relationships. One hundred thirty-three compounds were considered: they were either collected from literature or newly synthesized in order to gain information about the less explored positions. To this end, various melatonin derivatives were prepared and their affinity for quail optic tecta melatonin receptor was tested. Compounds were aligned on the putative active conformation of melatonin proposed by our previously reported pharmacophore search, and their relative affinities were calculated from the displacement of 2-[125I]-iodomelatonin on different tissues expressing aMT receptors. Compounds were grouped into three sets according to their topology. Subset A: melatonin-like compounds; subset B: N-acyl-2-amino-8-methoxytetralins and related compounds; subset C:N-acyl-phenylalkylamines and related compounds. CoMFA models were derived for each set, using the steric, electrostatic, and lipophilic fields as structural descriptors; the PLS analyses were characterized by good statistical parameters, taking into account the heterogeneity of the binding data, obtained with different experimental protocols. From the CoMFA model for the melatonin-like compounds, besides the well-known positive effect of 2-substitution, a low steric tolerance for substituents in 1, 6, and 7, and a negative effect of electron-rich 4-substituents were observed; the information provided by the newly synthesized compounds was essential for these results. Moreover, a comprehensive model for the 133 compounds, accounting for a common alignment and a common mode of interaction at the melatonin receptor, was derived (Q2 = 0.769, R2 = 0.905). This model validates our previously reported pharmacophore search and offers a clear depiction of the structure-affinity relationships for the melatonin receptor ligands.
为了建立定量构效关系，将比较分子力场分析（CoMFA）方法应用于褪黑素受体配体。共考虑了133种化合物：它们要么是从文献中收集的，要么是新合成的，以便获取关于较少研究位置的信息。为此，制备了各种褪黑素衍生物，并测试了它们对鹌鹑视顶盖褪黑素受体的亲和力。根据我们先前报道的药效团搜索提出的褪黑素假定活性构象对化合物进行比对，并根据2-[125I] - 碘褪黑素在表达aMT受体的不同组织上的位移计算它们的相对亲和力。根据拓扑结构将化合物分为三组。子集A：褪黑素样化合物；子集B：N-酰基-2-氨基-8-甲氧基四氢萘及其相关化合物；子集C：N-酰基-苯基烷基胺及其相关化合物。使用空间、静电和脂溶性场作为结构描述符，为每组推导CoMFA模型；考虑到通过不同实验方案获得的结合数据的异质性，偏最小二乘法（PLS）分析具有良好的统计参数。从褪黑素样化合物的CoMFA模型中，除了众所周知的2-取代的积极作用外，还观察到1、6和7位取代基的空间耐受性低，以及富电子4-取代基的负面影响；新合成化合物提供的信息对这些结果至关重要。此外，还推导了一个针对133种化合物的综合模型，该模型考虑了褪黑素受体上的共同比对和共同相互作用模式（Q2 = 0.769，R2 = 0.905）。该模型验证了我们先前报道的药效团搜索，并清晰地描绘了褪黑素受体配体的构效关系。
