3D QSAR analyses-guided rational design of novel ligands for the (α4)2(β2)3 nicotinic acetylcholine receptor

被引:49
作者
Gohlke, H
Schwarz, S
Gündisch, D
Tilotta, MC
Weber, A
Wegge, T
Seitz, G
机构
[1] Univ Marburg, Inst Pharmazeut Chem, D-35032 Marburg, Germany
[2] Univ Bonn, Inst Pharmazeut Chem, D-53115 Bonn, Germany
关键词
D O I
10.1021/jm020859m
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Three-dimensional quantitative structure-activity relationship methods, the comparative molecular field analysis (CoMFA) and the comparative molecular similarity indices analysis (CoMSIA), were applied using a training set of 45 ligands of the (alpha4)(2)(beta2)(3) nicotinic acetylcholine receptor (nAChR). All compounds are related to (-)-epibatidine, (-)-cytisine, (+)-anatoxin-a, and (-)-ferruginine, and additionally, novel diazabicyclo[4.2.1]nonane- and quinuclidin-2-ene-based structures were included. Their biological data have been determined by utilizing the same experimental protocol. Statistically reliable models of good predictive power (CoMFA r(2) = 0.928, q(2) = 0.692, no. of components = 3; CoMSIA r(2) = 0.899, q(2) = 0.701, no. of components = 3) were achieved. The results obtained were graphically interpreted in terms of field contribution maps. Hence, physicochemical. determinants of binding, such as steric and electrostatic and, for the first time, hydrophobic, hydrogen bond donor, and hydrogen bond acceptor properties, were mapped back onto the molecular structures of a set of nAChR modulators. In particular, changes in the binding affinity of the modulators as a result of modifications in the aromatic ring systems could be rationalized by the steric, electrostatic, hydrophobic, and hydrogen bond acceptor properties. These results were used to guide the rational design of new nAChR ligands such as 48-52 and 54, which were subsequently synthesized for the first time and tested. Key steps of our synthetic approaches were successfully applied Stille and Suzuki cross-coupling reactions. Predictive r(2) values of 0.614 and 0.660 for CoMFA and CoMSIA, respectively, obtained for 22 in part previously unknown ligands for the (alpha4)(2)(beta2)(3) subtype, demonstrate the high quality of the 3D QSAR models.
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收藏
页码:2031 / 2048
页数:18
相关论文
共 77 条
[61]   EPIBATIDINE - A NOVEL (CHLOROPYRIDYL)AZABICYCLOHEPTANE WITH POTENT ANALGESIC ACTIVITY FROM AN ECUADORIAN POISON FROG [J].
SPANDE, TF ;
GARRAFFO, HM ;
EDWARDS, MW ;
YEH, HJC ;
PANNELL, L ;
DALY, JW .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1992, 114 (09) :3475-3478
[62]  
Stahle L, 1988, Prog Med Chem, V25, P291, DOI 10.1016/S0079-6468(08)70281-9
[63]  
STEHL A, 2002, THESIS PHILLIPS U MA
[64]   SPECIAL ISSUE - MOPAC - A SEMIEMPIRICAL MOLECULAR-ORBITAL PROGRAM [J].
STEWART, JJP .
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 1990, 4 (01) :1-45
[65]  
STEWART JJP, MOPAC GENERAL MOL OR
[66]   THE PALLADIUM-CATALYZED CROSS-COUPLING REACTIONS OF ORGANOTIN REAGENTS WITH ORGANIC ELECTROPHILES [J].
STILLE, JK .
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION IN ENGLISH, 1986, 25 (06) :508-523
[67]  
Thibaut U., 1993, 3D QSAR DRUG DESIGN, P711
[68]   An improved nicotinic pharmacophore and a stereoselective CoMFA-model for nicotinic agonists acting at the central nicotinic acetylcholine receptors labelled by [3H]-N-methylcarbamylcholine [J].
Tonder, JE ;
Olesen, PH ;
Hansen, JB ;
Begtrup, M ;
Pettersson, I .
JOURNAL OF COMPUTER-AIDED MOLECULAR DESIGN, 2001, 15 (03) :247-258
[69]   Agonists at the α4β2 nicotinic acetylcholine receptors:: Structure-activity relationships and molecular modelling [J].
Tonder, JE ;
Olesen, PH .
CURRENT MEDICINAL CHEMISTRY, 2001, 8 (06) :651-674
[70]  
*TRIP INC, 2000, SYBYL MOL MOD SOFTW