A comparative QSAR analysis of acetylcholinesterase inhibitors currently studied for the treatment of Alzheimer's disease.

Considering the relevance of acetylcholinesterase inhibitors as potential agents for the treatment of the Alzheimer's disease, we have undertaken a comparative QSAR analysis aimed at individuating the physico-chemical properties governing the inhibitory activity of such compounds. The QSAR equations for 13 series of derivatives have been calculated and discussed. The series studied are all those we found in the literature suitable for a QSAR analysis and represent the three main classes of acetylcholinesterase inhibitors currently investigated, namely, physostigmine analogues, 1,2,3,4-tetrahydroacridines and benzylamines. The equations we obtained show that, within each class, the main physico-chemical properties affecting the inhibitory activity are almost the same for all the series and can be individuated by the use of proper parameters. The conclusions of this study can be summarized as follows: (a) hydrophobicity plays a critical role in both the physostigmine- and the benzylamine-derived classes; (b) electronic effects are important for the interactions carried out by the variable portion of benzylamine derivatives; and (c) steric factors are also significant, but, as in other cases, the collinearity between steric and hydrophobic parameters does not allow one to draw any final conclusion.

[1]  N. Greig,et al.  Phenylcarbamates of (-)-Eseroline, (-)-N1-Noreseroline and (-)- Physovenol: Selective Inhibitors of Acetyl and/or Butyrylcholinesterase. , 1993 .

[2]  T Nakamura,et al.  Novel piperidine derivatives. Synthesis and anti-acetylcholinesterase activity of 1-benzyl-4-[2-(N-benzoylamino)ethyl]piperidine derivatives. , 1990, Journal of medicinal chemistry.

[3]  R. Langridge,et al.  Quantitative structure-activity relationships and molecular graphics in ligand receptor interactions: amidine inhibition of trypsin. , 1986, Molecular pharmacology.

[4]  A. Brossi,et al.  Synthesis and anticholinesterase activity of (-)-N1-norphysostigmine, (-)-eseramine, and other N(1)-substituted analogues of (-)-physostigmine. , 1988, Journal of Medicinal Chemistry.

[5]  P. S. Magee.  10 - Chemicals Affecting Insects and Mites , 1983 .

[6]  A. Leo,et al.  Substituent constants for correlation analysis in chemistry and biology , 1979 .

[7]  R. Rydel,et al.  Therapeutic approaches related to amyloid-beta peptide and Alzheimer's disease. , 1995, Journal of medicinal chemistry.

[8]  Yuan-Ping Pang,et al.  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 , 1994, J. Comput. Aided Mol. Des..

[9]  D. Liston,et al.  Syntheses, resolution, and structure-activity relationships of potent acetylcholinesterase inhibitors: 8-carbaphysostigmine analogues. , 1992, Journal of medicinal chemistry.

[10]  J. Topliss.  Quantitative structure-activity relationships of drugs , 1983 .

[11]  P. Taylor,et al.  Role of the peripheral anionic site on acetylcholinesterase: inhibition by substrates and coumarin derivatives. , 1991, Molecular pharmacology.

[12]  S. Gupta.  QSAR studies on enzyme inhibitors , 1987 .

[13]  G M Steinberg,et al.  A hydrophobic binding site in acetylcholinesterase. , 1975, Journal of medicinal chemistry.

[14]  J A McCammon,et al.  Computer-aided molecular design. , 1987, Science.

[15]  N. Greig,et al.  Phenserine and ring C hetero‐analogues: Drug candidates for the treatment of Alzheimer's disease , 1995, Medicinal research reviews.

[16]  W. Welsh,et al.  A comparative molecular field analysis study of N-benzylpiperidines as acetylcholinesterase inhibitors. , 1996, Journal of medicinal chemistry.

[17]  H. Sugimoto,et al.  Synthesis and structure-activity relationships of acetylcholinesterase inhibitors: 1-benzyl-4-(2-phthalimidoethyl)piperidine and related derivatives. , 1992, Journal of medicinal chemistry.

[18]  Central Cholinergic Agents. I. Potent Acetylcholinesterase Inhibitors, 2-[ω-[N-Alkyl-N-(ω-phenyl-alkyl)amino]alkyl]-1H-isoindole-1,3(2H)-diones, Based on a New Hypothesis of the Enzyme's Active Site , 1991 .

[19]  S. Dei,et al.  The medicinal chemistry of Alzheimer's and Alzheimer-like diseases with emphasis on the cholinergic hypothesis. , 1995, Farmaco.

[20]  J. Sussman,et al.  Three-dimensional structure of acetylcholinesterase and of its complexes with anticholinesterase drugs. , 1993, Chemico-biological interactions.

[21]  A J Hopfinger,et al.  QSAR analyses of the substituted indanone and benzylpiperidine rings of a series of indanone-benzylpiperidine inhibitors of acetylcholinesterase. , 1992, Journal of medicinal chemistry.

[22]  R. Bartus,et al.  The cholinergic hypothesis of geriatric memory dysfunction. , 1982, Science.

[23]  Aalt Bast,et al.  Comprehensive medicinal chemistry , 1991 .

[24]  Mario G. Cardozo,et al.  Conformational analyses and molecular-shape comparisons of a series of indanone-benzylpiperidine inhibitors of acetylcholinesterase , 1992 .

[25]  Eugene D. Thorsett,et al.  Chapter 21. Alzheimer's Disease: Current Therapeutic Approaches , 1993 .

[26]  M Briley,et al.  Novel [2-(4-piperidinyl)ethyl](thio)ureas: synthesis and antiacetylcholinesterase activity. , 1994, Journal of medicinal chemistry.

[27]  K. Davis,et al.  9-Amino-1,2,3,4-tetrahydroacridin-1-ols: synthesis and evaluation as potential Alzheimer's disease therapeutics. , 1989, Journal of medicinal chemistry.

[28]  C. Hansch.  Quantitative structure-activity relationships and the unnamed science , 1993 .

[29]  Yuan-Ping Pang,et al.  Prediction of the binding sites of huperzine A in acetylcholinesterase by docking studies , 1994, J. Comput. Aided Mol. Des..

[30]  A. Goldman,et al.  Atomic structure of acetylcholinesterase from Torpedo californica: a prototypic acetylcholine-binding protein , 1991, Science.

[31]  Emanuela Licandro,et al.  Synthesis and structure-activity relationships of new acetylcholinesterase inhibitors: Morpholinoalkylcarbamoyloxyeseroline derivatives , 1995 .

[32]  R. Metcalf,et al.  Pesticidal Activity and Structure, Structure and Insecticidal Activity of Some Diethyl Substituted Phenyl Phosphates , 1956 .

[33]  J. Blake,et al.  Novel benzisoxazole derivatives as potent and selective inhibitors of acetylcholinesterase. , 1994, Journal of medicinal chemistry.