Cardozo M G, Iimura Y, Sugimoto H, Yamanishi Y, Hopfinger A J
Department of Medicinal Chemistry and Pharmacognosy, University of Illinois, Chicago 60680.
J Med Chem. 1992 Feb 7;35(3):584-9. doi: 10.1021/jm00081a022.
QSAR analyses have been performed on the substituted indanone and benzylpiperidine ring substructures of a set of acetylcholinesterase, AChE, inhibitors of which 1-benzyl-4-[(5,6-dimethoxy-1-oxoindan-2-yl)methyl]piperidine hydrochloride is a potent in vitro and ex vivo inhibitor. The method of molecular decomposition-recomposition was used to define the sets of molecular substructures and corresponding in vitro inhibition databases. A QSAR involving the magnitude of the dipole moment, the highest occupied molecular orbital (HOMO) energy, and a specific pi-orbital wave function coefficient of the substituted indanone ring substructure was constructed and found to be significant. The absence of any molecular-shape or bulk term in the QSAR, coupled with some of the relatively large substituents used to construct the QSAR, suggests considerable space is available around the indanone ring during the inhibition process. A set of QSARs were constructed and evaluated for substituents on the aromatic ring of the benzylpiperidine substructure. The most significant QSAR involves a representation of molecular shape, the largest principal moment of inertia, and the HOMO of the substituted aromatic ring. It appears that upon binding the receptor "wall" is closely fit around the benzyl ring, especially near the para position. Overall, the QSAR analysis suggests inhibition potency can be better enhanced by substitution on the indanone ring, as compared to the aromatic sites of the benzylpiperidine ring. Moreover, inhibition potency can be rapidly diminished, presumably through steric interactions with the receptor surface of AChE, by substitution of moderate to large groups on the benzyl ring, particularly at the para position.
已对一组乙酰胆碱酯酶（AChE）抑制剂的取代茚满酮和苄基哌啶环亚结构进行了定量构效关系（QSAR）分析，其中盐酸1-苄基-4-[(5,6-二甲氧基-1-氧代茚满-2-基)甲基]哌啶是一种有效的体外和体内抑制剂。采用分子分解-重组方法定义分子亚结构集和相应的体外抑制数据库。构建了一个涉及偶极矩大小、最高占据分子轨道（HOMO）能量和取代茚满酮环亚结构的特定π轨道波函数系数的QSAR，发现其具有显著性。QSAR中没有任何分子形状或体积项，再加上用于构建QSAR的一些相对较大的取代基，这表明在抑制过程中茚满酮环周围有相当大的空间。构建并评估了一组关于苄基哌啶亚结构芳香环上取代基的QSAR。最显著的QSAR涉及分子形状的表示、最大主惯性矩和取代芳香环的HOMO。似乎在结合时，受体“壁”紧密贴合在苄基环周围，尤其是在对位附近。总体而言，QSAR分析表明，与苄基哌啶环的芳香位点相比，通过在茚满酮环上进行取代可以更好地提高抑制效力。此外，通过在苄基环上，特别是在对位上取代中等至大的基团，可能通过与AChE受体表面的空间相互作用，抑制效力会迅速降低。
