Rodolphe Razet - Academia.edu (original) (raw)
Papers by Rodolphe Razet
L'objectif de ce travail a ete la recherche de nouveaux analogues de la bicuculline (un phtal... more L'objectif de ce travail a ete la recherche de nouveaux analogues de la bicuculline (un phtalido-isoquinoleine) depourvus du noyau phenyle d qui soient selectifs pour un des sous-types des recepteurs gaba a present dans le systeme nerveux central. C'est par des condensations entre des dienes silyloxy (furanes et pyrroles) et des 3,4-dihydroisoquinoleines ou des isoquinoleines activees par divers electrophiles selon une reaction de mannich vinylogue que de nombreux analogues ont pu etre prepares. Ces composes de nature lactonique (butenolides et butyrolactones) ou lactamique (pyrrolinones et butyrolactames) substitues en position par un noyau isoquinoleine n-fonctionnalise ont fait l'objet d'une analyse structurale et pharmacologique approfondie. Les resultats de radiocristallographie et les donnees recueillies par rmn ont ete tres utiles pour cette analyse structurale, surtout du point de vue stereochimique. Les essais d'electrophysiologie et de liaison effectues...
![Research paper thumbnail of 5-[1‘-(2‘-N-Arylsulfonyl-1‘,2‘,3‘,4‘-tetrahydroisoquinolyl)]-4,5-dihydro-2(3H)-furanones: Positive Allosteric Modulators of the GABAA Receptor with a New Mode of Action](https://attachments.academia-assets.com/103658330/thumbnails/1.jpg)
](Journal of Medicinal Chemistry, 2000
Introduction. γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central ... more Introduction. γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system. It acts at the GABA A receptor, a pentameric supramolecular complex which forms a ligand-gated ion channel controlling chloride ion flux in the neuron. Binding of GABA to its recognition site on the receptor has as principal effect the opening of the channel, allowing chloride ions to flow, leading to inhibition of neuronal activity. The subunits composing the GABA A receptor have been classified as R, , γ, δ, , π, and, more recently, θ based on sequence homology. 1-6 These subunits are also generally present in the form of several isoforms (e.g. R1, R2, etc.), leading to a potentially high level of receptor heterogeneity, though the most common receptor composition has been found to consist of R1, 2, and γ2 subunits. 7,8 In addition to the heterogeneity of the GABA A receptor system, each receptor also has a variety of allosteric sites, which, upon binding of their specific ligands, leads to modulation of GABA activity. 9 Thus, compounds which stimulate GABA-induced chloride ion currents are referred to as positive allosteric modulators. These include the therapeutically useful benzodiazepines which bind to the benzodiazepine recognition site. The latter in fact also binds a wide variety of compounds structurally unrelated to benzodiazepines and which have the same potentiating effect on GABA. 10 Other positive allosteric binding sites of the GABA A receptor include the barbiturate, neurosteroid, and loreclezole sites. On the other hand, negative allosteric modulation of the GABA A receptor (that is, inhibition of the neuroinhibitory action of GABA) is also possible with certain ligands as, for example, certain-carbolines which bind to the benzodiazepine recognition site. 10,11 Positive allosteric modulators of the GABA receptor generally display, to varying degrees, anticonvulsant, anxiolytic, sedative-hypnotic, anesthetic, and musclerelaxant activities. Certain undesirable side effects are
L'objectif de ce travail a ete la recherche de nouveaux analogues de la bicuculline (un phtal... more L'objectif de ce travail a ete la recherche de nouveaux analogues de la bicuculline (un phtalido-isoquinoleine) depourvus du noyau phenyle d qui soient selectifs pour un des sous-types des recepteurs gaba a present dans le systeme nerveux central. C'est par des condensations entre des dienes silyloxy (furanes et pyrroles) et des 3,4-dihydroisoquinoleines ou des isoquinoleines activees par divers electrophiles selon une reaction de mannich vinylogue que de nombreux analogues ont pu etre prepares. Ces composes de nature lactonique (butenolides et butyrolactones) ou lactamique (pyrrolinones et butyrolactames) substitues en position par un noyau isoquinoleine n-fonctionnalise ont fait l'objet d'une analyse structurale et pharmacologique approfondie. Les resultats de radiocristallographie et les donnees recueillies par rmn ont ete tres utiles pour cette analyse structurale, surtout du point de vue stereochimique. Les essais d'electrophysiologie et de liaison effectues...
Journal of Medicinal Chemistry, 2000
Introduction. γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central ... more Introduction. γ-Aminobutyric acid (GABA) is the major inhibitory neurotransmitter of the central nervous system. It acts at the GABA A receptor, a pentameric supramolecular complex which forms a ligand-gated ion channel controlling chloride ion flux in the neuron. Binding of GABA to its recognition site on the receptor has as principal effect the opening of the channel, allowing chloride ions to flow, leading to inhibition of neuronal activity. The subunits composing the GABA A receptor have been classified as R, , γ, δ, , π, and, more recently, θ based on sequence homology. 1-6 These subunits are also generally present in the form of several isoforms (e.g. R1, R2, etc.), leading to a potentially high level of receptor heterogeneity, though the most common receptor composition has been found to consist of R1, 2, and γ2 subunits. 7,8 In addition to the heterogeneity of the GABA A receptor system, each receptor also has a variety of allosteric sites, which, upon binding of their specific ligands, leads to modulation of GABA activity. 9 Thus, compounds which stimulate GABA-induced chloride ion currents are referred to as positive allosteric modulators. These include the therapeutically useful benzodiazepines which bind to the benzodiazepine recognition site. The latter in fact also binds a wide variety of compounds structurally unrelated to benzodiazepines and which have the same potentiating effect on GABA. 10 Other positive allosteric binding sites of the GABA A receptor include the barbiturate, neurosteroid, and loreclezole sites. On the other hand, negative allosteric modulation of the GABA A receptor (that is, inhibition of the neuroinhibitory action of GABA) is also possible with certain ligands as, for example, certain-carbolines which bind to the benzodiazepine recognition site. 10,11 Positive allosteric modulators of the GABA receptor generally display, to varying degrees, anticonvulsant, anxiolytic, sedative-hypnotic, anesthetic, and musclerelaxant activities. Certain undesirable side effects are