Pharmacophore Modeling as an Efficient Tool in the Discovery of Novel Noncompetitive AMPA Receptor Antagonists

A three-dimensional pharmacophore model for the binding of noncompetitive AMPA receptor antagonists was developed in order to map common structural features of highly active compounds. This hypothesis, which consists of two hydrophobic regions, one hydrogen bond acceptor and one aromatic region, was successfully used as framework for the design of a new class of allosteric modulators containing a tetrahydroisoquinoline skeleton and for in silico screening. The promising biological results suggested that the identified molecules might be useful "lead compounds" for future drug development.

[1]  A. Ganong,et al.  Functional characterization of CP-465,022, a selective, noncompetitive AMPA receptor antagonist , 2002, Neuropharmacology.

[2]  Andrew Smellie,et al.  Poling: Promoting conformational variation , 1995, J. Comput. Chem..

[3]  R. B. Carter,et al.  Synthesis of 7,8-(methylenedioxy)-1-phenyl-3,5-dihydro-4H-2, 3-benzodiazepin-4-ones as novel and potent noncompetitive AMPA receptor antagonists. , 1998, Journal of Medicinal Chemistry.

[4]  G. De Sarro,et al.  Synthesis and evaluation of pharmacological and pharmacokinetic properties of 11H-[1,2,4]triazolo[4,5-c][2,3]benzodiazepin-3(2H)-ones. , 2000, Journal of medicinal chemistry.

[5]  A. Ganong,et al.  Atropisomeric quinazolin-4-one derivatives are potent noncompetitive alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists. , 2001, Bioorganic & medicinal chemistry letters.

[6]  C. Valenzuela,et al.  Allosteric modulators of the AMPA receptor: novel 6-substituted dihydrophthalazines. , 1999, Bioorganic & Medicinal Chemistry Letters.

[7]  M. Rogawski,et al.  AMPA receptors in epilepsy and as targets for antiepileptic drugs. , 1999, Advances in neurology.

[8]  A. Constanti,et al.  1-Aryl-3,5-dihydro-4H-2,3-benzodiazepin-4-ones: novel AMPA receptor antagonists. , 1997, Journal of Medicinal Chemistry.

[9]  K. A. Jones,et al.  Substituted 1,2-dihydrophthalazines: potent, selective, and noncompetitive inhibitors of the AMPA receptor. , 1996, Journal of Medicinal Chemistry.

[10]  R. Gitto,et al.  AMPA receptor antagonists , 1999 .

[11]  R. Dingledine,et al.  The glutamate receptor ion channels. , 1999, Pharmacological reviews.

[12]  S. Nikam,et al.  AMPA receptor antagonists. , 2001, Current medicinal chemistry.

[13]  F. Menniti,et al.  Quinazolin-4-one alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists: structure-activity relationship of the C-2 side chain tether. , 2001, Journal of medicinal chemistry.

[14]  M. Karplus,et al.  CHARMM: A program for macromolecular energy, minimization, and dynamics calculations , 1983 .

[15]  P. Krogsgaard‐Larsen,et al.  Ligands for glutamate receptors: design and therapeutic prospects. , 2000, Journal of medicinal chemistry.

[16]  M. Rogawski,et al.  GYKI 52466, a 2,3-benzodiazepine, is a highly selective, noncompetitive antagonist of AMPA/kainate receptor responses , 1993, Neuron.

[17]  I. Tarnawa,et al.  Structural analogues of some highly active non-competitive AMPA antagonists. , 2000, Bioorganic & medicinal chemistry letters.

[18]  A. Constanti,et al.  3,5-Dihydro-4H-2,3-benzodiazepine-4-thiones: a new class of AMPA receptor antagonists. , 1998, Journal of medicinal chemistry.

[19]  G. De Sarro,et al.  GYKI 52466 and related 2,3-benzodiazepines as anticonvulsant agents in DBA/2 mice. , 1995, European journal of pharmacology.