Synthesis, in vitro pharmacology, and molecular modeling of very potent tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer's disease

被引:108
作者
Camps, P
El Achab, R
Görbig, DM
Morral, J
Muñoz-Torrero, D
Badia, A
Baños, JE
Vivas, NM
Barril, X
Orozco, M
Luque, FJ
机构
[1] Univ Barcelona, Fac Farm, Quim Farmaceut Lab, E-08028 Barcelona, Spain
[2] Univ Autonoma Barcelona, Fac Med, Dept Farmacol & Terapeut, E-08193 Barcelona, Spain
[3] Univ Barcelona, Fac Farm, Dept Fisicoquim, E-08028 Barcelona, Spain
[4] Univ Barcelona, Fac Quim, Dept Bioquim, E-08028 Barcelona, Spain
关键词
D O I
10.1021/jm980620z
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
Eleven new 12-amino-6,7,10,11-tetrahydro-7,11-methanocycloocta[b]quinoline derivatives [tacrine (THA)-huperzine A hybrids, rac-21-31] have been synthesized as racemic mixtures and tested as acetylcholinesterase (AChE) inhibitors. For derivatives unsubstituted at the benzene ring, the highest activity was obtained for the g-ethyl. derivative rac-20, previously prepared by our group. More bulky substituents at position 9 led to less active compounds, although some of them [9-isopropyl (rac-22), 9-allyl (rac-23), and 9-phenyl (rac-26)] show activities similar to that of THA. Substitution at position 1 or 3 with methyl or fluorine atoms always led to more active compounds. Among them, the highest activity was observed for the 3-fluoro-9-methyl derivative rac-28 [about 15-fold more active than THA and about 9-fold more active than (-)-huperzine A]. The activity of some THA-huperzine A hybrids (rac-19, rac-20, rac-28, and rac-30), which were separated into their enantiomers by chiral medium-pressure liquid chromatography (chiral MPLC), using microcrystalline cellulose triacetate as the chiral stationary phase, showed the eutomer to be always the levorotatory enantiomer, their activity being roughly double that of the corresponding racemic mixture, the distomer being much less active. Also, the activity of some of these compounds inhibiting butyrylcholinesterase (BChE) was tested. Most of them [rac-27-31, (-)-28, and (-)-30], which are more active than (-)-huperzine A as AChE inhibitors, turned out to be quite selective for AChE, although not so selective as (-)-huperzine A. Most of the tested compounds 19-31 proved to be much more active than THA in reversing the neuromuscular blockade induced by d-tubocurarine. Molecular modeling of the interaction of these compounds with AChE from Torpedo californica showed them to interact as truly THA-huperzine A hybrids: the 4-aminoquinoline subunit of (-)-19 occupies the same position of the corresponding subunit in THA, while its bicyclo[3.3.1]nonadiene substructure roughly occupies the same position of the corresponding substructure in (-)-huperzine A, in agreement with the absolute configurations of(-)-19 and (-)-huperzine A.
引用
收藏
页码:3227 / 3242
页数:16
相关论文
共 70 条
[1]   SYNTHESIS AND EVALUATION OF TACRINE-RELATED COMPOUNDS FOR THE TREATMENT OF ALZHEIMERS-DISEASE [J].
AGUADO, F ;
BADIA, A ;
BANOS, JE ;
BOSCH, F ;
BOZZO, C ;
CAMPS, P ;
CONTRERAS, J ;
DIERSSEN, M ;
ESCOLANO, C ;
GORBIG, DM ;
MUNOZTORRERO, D ;
PUJOL, MD ;
SIMON, M ;
VAZQUEZ, MT ;
VIVAS, NM .
EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 1994, 29 (03) :205-221
[2]   MECHANISM OF INHIBITION OF CHOLINESTERASES BY HUPERZINE-A [J].
ASHANI, Y ;
PEGGINS, JO ;
DOCTOR, BP .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1992, 184 (02) :719-726
[3]   Synthesis and evaluation of tacrine-huperzine A hybrids as acetylcholinesterase inhibitors of potential interest for the treatment of Alzheimer's disease [J].
Badia, A ;
Banos, JE ;
Camps, P ;
Contreras, J ;
Gorbig, DM ;
Munoz-Torrero, D ;
Simon, M ;
Vivas, NM .
BIOORGANIC & MEDICINAL CHEMISTRY, 1998, 6 (04) :427-440
[4]  
BANOS J, 1988, ARCH INT PHARMACOD T, V293, P219
[5]   Is there a rationale for the use of acetylcholinesterase inhibitors in the therapy of Alzheimer's disease? [J].
Benzi, G ;
Moretti, A .
EUROPEAN JOURNAL OF PHARMACOLOGY, 1998, 346 (01) :1-13
[6]  
*BIOS TECHN, 1993, INS 2
[7]   Some acyl derivatives of homoanthranilic nitrile, and the 7-methyl-4-ketodihydro-quinazolines prepared therefrom [J].
Bogert, MT ;
Hoffman, A .
JOURNAL OF THE AMERICAN CHEMICAL SOCIETY, 1905, 27 (10) :1293-1301
[8]   COMPARATIVE EFFECTS OF VELNACRINE, TACRINE AND PHYSOSTIGMINE ON THE TWITCH RESPONSES IN THE RAT PHRENIC-HEMIDIAPHRAGM PREPARATION [J].
BOSCH, F ;
MORALES, M ;
BADIA, A ;
BANOS, JE .
GENERAL PHARMACOLOGY, 1993, 24 (05) :1101-1105
[9]  
Bowman W.C., 1990, PHARM NEUROMUSCULAR
[10]   PRESYNAPTIC RECEPTORS IN THE NEUROMUSCULAR-JUNCTION [J].
BOWMAN, WC ;
PRIOR, C ;
MARSHALL, IG .
ANNALS OF THE NEW YORK ACADEMY OF SCIENCES, 1990, 604 :69-81