A comparative molecular field analysis study of N-benzylpiperidines as acetylcholinesterase inhibitors

被引:72
作者
Tong, W
Collantes, ER
Chen, Y
Welsh, WJ
机构
[1] UNIV MISSOURI,DEPT CHEM,ST LOUIS,MO 63121
[2] UNIV MISSOURI,CTR MOLEC ELECTR,ST LOUIS,MO 63121
关键词
D O I
10.1021/jm950704x
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
A series of 1-benzyl-4-[2-(N-benzoylamino)ethyl]pipe derivatives and ofN-benzylpiperidine benzisoxazoles has been investigated using the comparative molecular field analysis (CoMFA) approach. These compounds have been found to inhibit the metabolic breakdown of the neurotransmitter acetylcholine (ACh) by the enzyme acetylcholinesterase (AChE) and hence alleviate memory deficits in patients with Alzheimer's Disease by potentiating cholinergic transmission. Development of the CoMFA model considered two separate alignments: (i) alignment I which emphasized the electrostatic fitting of the subject compounds and (ii) alignment II which emphasized their steric fitting. In addition, the inhibitor compounds were considered both as neutral species and as N-piperidine-protonated species. The resulting 3D-QSAR indicates a strong correlation between the inhibitory activity of these N-benzylpiperidines and the steric and electronic factors which modulate their biochemical activity. A CoMFA model with considerable predictive ability was obtained.
引用
收藏
页码:380 / 387
页数:8
相关论文
共 22 条
[11]  
KUMAR V, 1991, INT J CLIN PHARM TH, V29, P23
[12]   QSAR OF CONFORMATIONALLY FLEXIBLE MOLECULES - COMPARATIVE MOLECULAR-FIELD ANALYSIS OF PROTEIN-TYROSINE KINASE INHIBITORS [J].
NICKLAUS, MC ;
MILNE, GWA ;
BURKE, TR .
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 1992, 6 (05) :487-504
[13]   PREDICTION OF THE BINDING-SITE OF 1-BENZYL-4-[(5,6-DIMETHOXY-1-INDANON-2-YL)METHYL]PIPERIDINE IN ACETYLCHOLINESTERASE BY DOCKING STUDIES WITH THE SYSDOC PROGRAM [J].
PANG, YP ;
KOZIKOWSKI, AP .
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 1994, 8 (06) :683-693
[14]   THE CHOLINERGIC HYPOTHESIS - 10 YEARS ON [J].
PERRY, EK .
BRITISH MEDICAL BULLETIN, 1986, 42 (01) :63-69
[15]   SYNTHESIS AND STRUCTURE-ACTIVITY-RELATIONSHIPS OF ACETYLCHOLINESTERASE INHIBITORS - 1-BENZYL-4-(2-PHTHALIMIDOETHYL)PIPERIDINE AND RELATED DERIVATIVES [J].
SUGIMOTO, H ;
TSUCHIYA, Y ;
SUGUMI, H ;
HIGURASHI, K ;
KARIBE, N ;
IIMURA, Y ;
SASAKI, A ;
ARAKI, S ;
YAMANISHI, Y ;
YAMATSU, K .
JOURNAL OF MEDICINAL CHEMISTRY, 1992, 35 (24) :4542-4548
[16]   NOVEL PIPERIDINE-DERIVATIVES - SYNTHESIS AND ANTIACETYLCHOLINESTERASE ACTIVITY OF 1-BENZYL-4-[2-(N-BENZOYLAMINO)ETHYL]PIPERIDINE DERIVATIVES [J].
SUGIMOTO, H ;
TSUCHIYA, Y ;
SUGUMI, H ;
HIGURASHI, K ;
KARIBE, N ;
IIMURA, Y ;
SASAKI, A ;
KAWAKAMI, Y ;
NAKAMURA, T ;
ARAKI, S ;
YAMANISHI, Y ;
YAMATSU, K .
JOURNAL OF MEDICINAL CHEMISTRY, 1990, 33 (07) :1880-1887
[17]   ATOMIC-STRUCTURE OF ACETYLCHOLINESTERASE FROM TORPEDO-CALIFORNICA - A PROTOTYPIC ACETYLCHOLINE-BINDING PROTEIN [J].
SUSSMAN, JL ;
HAREL, M ;
FROLOW, F ;
OEFNER, C ;
GOLDMAN, A ;
TOKER, L ;
SILMAN, I .
SCIENCE, 1991, 253 (5022) :872-879
[18]   INVITRO EFFECTS OF VARIOUS CHOLINESTERASE-INHIBITORS ON ACETYLCHOLINESTERASE AND BUTYRYLCHOLINESTERASE OF HEALTHY-VOLUNTEERS [J].
THOMSEN, T ;
ZENDEH, B ;
FISCHER, JP ;
KEWITZ, H .
BIOCHEMICAL PHARMACOLOGY, 1991, 41 (01) :139-141
[19]   NOVEL BENZISOXAZOLE DERIVATIVES AS POTENT AND SELECTIVE INHIBITORS OF ACETYLCHOLINESTERASE [J].
VILLALOBOS, A ;
BLAKE, JF ;
BIGGERS, CK ;
BUTLER, TW ;
CHAPIN, DS ;
CHEN, YPL ;
IVES, JL ;
JONES, SB ;
LISTON, DR ;
NAGEL, AA ;
NASON, DM ;
NIELSEN, JA ;
SHALABY, IA ;
WHITE, WF .
JOURNAL OF MEDICINAL CHEMISTRY, 1994, 37 (17) :2721-2734
[20]   3-DIMENSIONAL QSAR OF HUMAN-IMMUNODEFICIENCY-VIRUS-(I) PROTEASE INHIBITORS .1. A COMFA STUDY EMPLOYING EXPERIMENTALLY-DETERMINED ALIGNMENT RULES [J].
WALLER, CL ;
OPREA, TI ;
GIOLITTI, A ;
MARSHALL, GR .
JOURNAL OF MEDICINAL CHEMISTRY, 1993, 36 (26) :4152-4160