Samir Jegham | Sanofi - Academia.edu (original) (raw)
Papers by Samir Jegham
Neuropsychopharmacology, 2007
In this paper, we report on the pharmacological and functional profile of SSR180711 (1,4-Diazabic... more In this paper, we report on the pharmacological and functional profile of SSR180711 (1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester), a new selective a7 acetylcholine nicotinic receptor (n-AChRs) partial agonist. SSR180711 displays high affinity for rat and human a7 n-AChRs (K i of 2274 and 1471 nM, respectively). Ex vivo 3 [H]a-bungarotoxin binding experiments demonstrate that SSR180711 rapidly penetrates into the brain (ID 50 ¼ 8 mg/kg p.o.). In functional studies performed with human a7 n-AChRs expressed in Xenopus oocytes or GH4C1 cells, the compound shows partial agonist effects (intrinsic activity ¼ 51 and 36%, EC 50 ¼ 4.4 and 0.9 mM, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small a-bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic a7 n-AChRs, respectively. In mouse hippocampal slices, the compound increased the amplitude of both glutamatergic (EPSCs) and GABAergic (IPSCs) postsynaptic currents evoked in CA1 pyramidal cells. In rat and mouse hippocampal slices, a concentration of 0.3 mM of SSR180711 increased long-term potentiation (LTP) in the CA1 field. Null mutation of the a7 n-AChR gene totally abolished SSR180711-induced modulation of EPSCs, IPSCs and LTP in mice. Intravenous administration of SSR180711 strongly increased the firing rate of single ventral pallidum neurons, extracellularly recorded in anesthetized rats. In microdialysis experiments, administration of the compound (3-10 mg/kg i.p.) dosedependently increased extracellular acetylcholine (ACh) levels in the hippocampus and prefrontal cortex of freely moving rats. Together, these results demonstrate that SSR180711 is a selective and partial agonist at human, rat and mouse a7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus.
Cheminform, 2010
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Biological Psychiatry, 1997
The new era of monoamine oxidase inhibitors from molecular studies to clinical evaluation develop... more The new era of monoamine oxidase inhibitors from molecular studies to clinical evaluation development of a transdennaJ therapeutic system with an enhanced safety profile will be reported.
Tetrahedron Letters, 1998
Substituted chiral 3-aryl.2-oxazolidinones were readily prepared v/a regiospecific opening of cyc... more Substituted chiral 3-aryl.2-oxazolidinones were readily prepared v/a regiospecific opening of cyclic carbonates
Expert Opinion on Therapeutic Patents, 1998
ABSTRACT This patent update relates to monoamine oxidase inhibitors, covers the patent activity i... more ABSTRACT This patent update relates to monoamine oxidase inhibitors, covers the patent activity in this field for the last 3 - 5 years and focuses on the most relevant filings. Patents are classified according to the type of MAO inhibition: selective MAO-A and MAO-B inhibitors, and mixed and reversible MAO-A and MAO-B inhibitors.
Bioorganic & Medicinal Chemistry Letters, 1998
The capacity factor of eleven derivatives belonging to a prototype series of 3phenyloxazolidin-2-... more The capacity factor of eleven derivatives belonging to a prototype series of 3phenyloxazolidin-2-one, reversible MAO inhibitors, was measured and compared to the calculated log Pca~c using the CLIP package. We demonstrate that this Molecular Lipophilicity Potential (MLP) approach is a valuable tool to estimate log Pcalc of such compounds. O
Bioorganic & Medicinal Chemistry, 1999
Experimental and theoretical physico-chemical methods were used to investigate the interaction be... more Experimental and theoretical physico-chemical methods were used to investigate the interaction between several reversible monoamine oxidase A inhibitors in the oxazolidinone series and the active site of the enzyme. Phenyloxazolidinones include toloxatone and analogues, among which befloxatone was selected as drug candidate for the treatment of depression. Identification of the forces responsible for the crystal cohesion of befloxatone reveals functional groups that could interact with monoamine oxidase. Calculation of electronic properties of those compounds using ab initio molecular orbital methods lead to a description of the mode of interaction between befloxatone and the cofactor of the enzyme. Electronic absorption spectroscopy measurements confirm the hypothesis of a privileged interaction of phenyloxazolidinone-type inhibitors with the flavin cofactor of MAO. Additional sites of interaction with the protein core of MAO A are also examined with regard to the primary structure of the enzyme. As a result of this work, a model is proposed for the reversible inhibition of MAO A by befloxatone via long distance, reversible interactions with the flavin adenine dinucleotide (FAD) cofactor of the enzyme and with specific amino acids of the active site. This model is partially corroborated by experimental evidence and should be helpful in designing new potent inhibitors of monoamine oxidase.
Synthetic Communications, 1999
The Mitsunobu reaction of 1,3,4-oxadiazol-2(3H)-ones with alcohols leads to N3-alkylated products... more The Mitsunobu reaction of 1,3,4-oxadiazol-2(3H)-ones with alcohols leads to N3-alkylated products in high yields.
Synthetic Communications, 1999
The Mitsunobu reaction of 1,3,4-oxadiazol-2(3H)-ones with alcohols leads to N3-alkylated products... more The Mitsunobu reaction of 1,3,4-oxadiazol-2(3H)-ones with alcohols leads to N3-alkylated products in high yields.
![Research paper thumbnail of Synthesis and in vivo imaging properties of [ 11C]befloxatone: A novel highly potent positron emission tomography ligand for mono-amine oxidase-A](https://attachments.academia-assets.com/49462881/thumbnails/1.jpg)
](Bioorganic & Medicinal Chemistry Letters, 2003
Befloxatone (1, (5R)-5-(methoxymethyl)-3-[4-[(3R)-4,4,4-trifluoro-3-hydroxybutoxy]phenyl]-2-oxazo... more Befloxatone (1, (5R)-5-(methoxymethyl)-3-[4-[(3R)-4,4,4-trifluoro-3-hydroxybutoxy]phenyl]-2-oxazolidinone) is an oxazolidinone derivative belonging to a new generation of reversible and selective mono-amine oxidase-A (MAO-A) inhibitors. In vitro and ex vivo studies have demonstrated that befloxatone is a potent, reversible and competitive MAO-A inhibitor with potential antidepressant properties. Befloxatone (1) was labelled with carbon-11 (t 1=2 : 20.4 min) using [ 11 C]phosgene as reagent. Typically, starting from a 1.2 Ci (44.4 GBq) cyclotron-produced [ 11 C]CH 4 batch, 150-300 mCi (5.55-11.10 GBq) of [ 11 C]befloxatone ([ 11 C]-1) with a radiochemical-and chemical purity of more than 99% were routinely obtained within 20 min of radiosynthesis (including HPLC purification) with specific radioactivities of 500-2000 mCi/mmol (18.5-74.0 GBq/mmol). The results obtained in vivo with carbon-11-labelled befloxatone not only confirm the biochemical and pharmacological profile of befloxatone found in rodent and in human tissues but also point out [ 11 C]befloxatone as an excellent tool for the assessment of MAO-A binding sites using positron emission tomography, a high-resolution, sensitive, non-invasive and quantitative imaging technique. #
European Journal of Medicinal Chemistry, 1997
Different families of heterocycles containing 2 to 4 nitrogen atoms (oxadiazolones, tetrazoles an... more Different families of heterocycles containing 2 to 4 nitrogen atoms (oxadiazolones, tetrazoles and oxadiazinone derivatives, so-called diazoheterocyclics) are currently used as lead compounds for the design of reversible and selective monoamine oxidase B ( MAO-B) inhibitors. In order to clarify the mechanism of interaction of these molecules with the enzyme, we adopted a theoretical approach (ab initio calculations) and studied several structural and electronic properties of prototype molecules of the aryl diazo heterocyclic chemical series. This work provides a theoretical basis for structure-inhibition relationships in chemical series with potential IMAO-B properties.
Cheminform, 2010
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Neuropsychopharmacology, 2007
In this paper, we report on the pharmacological and functional profile of SSR180711 (1,4-Diazabic... more In this paper, we report on the pharmacological and functional profile of SSR180711 (1,4-Diazabicyclo[3.2.2]nonane-4-carboxylic acid, 4-bromophenyl ester), a new selective a7 acetylcholine nicotinic receptor (n-AChRs) partial agonist. SSR180711 displays high affinity for rat and human a7 n-AChRs (K i of 2274 and 1471 nM, respectively). Ex vivo 3 [H]a-bungarotoxin binding experiments demonstrate that SSR180711 rapidly penetrates into the brain (ID 50 ¼ 8 mg/kg p.o.). In functional studies performed with human a7 n-AChRs expressed in Xenopus oocytes or GH4C1 cells, the compound shows partial agonist effects (intrinsic activity ¼ 51 and 36%, EC 50 ¼ 4.4 and 0.9 mM, respectively). In rat cultured hippocampal neurons, SSR180711 induced large GABA-mediated inhibitory postsynaptic currents and small a-bungarotoxin sensitive currents through the activation of presynaptic and somato-dendritic a7 n-AChRs, respectively. In mouse hippocampal slices, the compound increased the amplitude of both glutamatergic (EPSCs) and GABAergic (IPSCs) postsynaptic currents evoked in CA1 pyramidal cells. In rat and mouse hippocampal slices, a concentration of 0.3 mM of SSR180711 increased long-term potentiation (LTP) in the CA1 field. Null mutation of the a7 n-AChR gene totally abolished SSR180711-induced modulation of EPSCs, IPSCs and LTP in mice. Intravenous administration of SSR180711 strongly increased the firing rate of single ventral pallidum neurons, extracellularly recorded in anesthetized rats. In microdialysis experiments, administration of the compound (3-10 mg/kg i.p.) dosedependently increased extracellular acetylcholine (ACh) levels in the hippocampus and prefrontal cortex of freely moving rats. Together, these results demonstrate that SSR180711 is a selective and partial agonist at human, rat and mouse a7 n-AChRs, increasing glutamatergic neurotransmission, ACh release and LTP in the hippocampus.
Cheminform, 2010
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
Biological Psychiatry, 1997
The new era of monoamine oxidase inhibitors from molecular studies to clinical evaluation develop... more The new era of monoamine oxidase inhibitors from molecular studies to clinical evaluation development of a transdennaJ therapeutic system with an enhanced safety profile will be reported.
Tetrahedron Letters, 1998
Substituted chiral 3-aryl.2-oxazolidinones were readily prepared v/a regiospecific opening of cyc... more Substituted chiral 3-aryl.2-oxazolidinones were readily prepared v/a regiospecific opening of cyclic carbonates
Expert Opinion on Therapeutic Patents, 1998
ABSTRACT This patent update relates to monoamine oxidase inhibitors, covers the patent activity i... more ABSTRACT This patent update relates to monoamine oxidase inhibitors, covers the patent activity in this field for the last 3 - 5 years and focuses on the most relevant filings. Patents are classified according to the type of MAO inhibition: selective MAO-A and MAO-B inhibitors, and mixed and reversible MAO-A and MAO-B inhibitors.
Bioorganic & Medicinal Chemistry Letters, 1998
The capacity factor of eleven derivatives belonging to a prototype series of 3phenyloxazolidin-2-... more The capacity factor of eleven derivatives belonging to a prototype series of 3phenyloxazolidin-2-one, reversible MAO inhibitors, was measured and compared to the calculated log Pca~c using the CLIP package. We demonstrate that this Molecular Lipophilicity Potential (MLP) approach is a valuable tool to estimate log Pcalc of such compounds. O
Bioorganic & Medicinal Chemistry, 1999
Experimental and theoretical physico-chemical methods were used to investigate the interaction be... more Experimental and theoretical physico-chemical methods were used to investigate the interaction between several reversible monoamine oxidase A inhibitors in the oxazolidinone series and the active site of the enzyme. Phenyloxazolidinones include toloxatone and analogues, among which befloxatone was selected as drug candidate for the treatment of depression. Identification of the forces responsible for the crystal cohesion of befloxatone reveals functional groups that could interact with monoamine oxidase. Calculation of electronic properties of those compounds using ab initio molecular orbital methods lead to a description of the mode of interaction between befloxatone and the cofactor of the enzyme. Electronic absorption spectroscopy measurements confirm the hypothesis of a privileged interaction of phenyloxazolidinone-type inhibitors with the flavin cofactor of MAO. Additional sites of interaction with the protein core of MAO A are also examined with regard to the primary structure of the enzyme. As a result of this work, a model is proposed for the reversible inhibition of MAO A by befloxatone via long distance, reversible interactions with the flavin adenine dinucleotide (FAD) cofactor of the enzyme and with specific amino acids of the active site. This model is partially corroborated by experimental evidence and should be helpful in designing new potent inhibitors of monoamine oxidase.
Synthetic Communications, 1999
The Mitsunobu reaction of 1,3,4-oxadiazol-2(3H)-ones with alcohols leads to N3-alkylated products... more The Mitsunobu reaction of 1,3,4-oxadiazol-2(3H)-ones with alcohols leads to N3-alkylated products in high yields.
Synthetic Communications, 1999
The Mitsunobu reaction of 1,3,4-oxadiazol-2(3H)-ones with alcohols leads to N3-alkylated products... more The Mitsunobu reaction of 1,3,4-oxadiazol-2(3H)-ones with alcohols leads to N3-alkylated products in high yields.
Bioorganic & Medicinal Chemistry Letters, 2003
Befloxatone (1, (5R)-5-(methoxymethyl)-3-[4-[(3R)-4,4,4-trifluoro-3-hydroxybutoxy]phenyl]-2-oxazo... more Befloxatone (1, (5R)-5-(methoxymethyl)-3-[4-[(3R)-4,4,4-trifluoro-3-hydroxybutoxy]phenyl]-2-oxazolidinone) is an oxazolidinone derivative belonging to a new generation of reversible and selective mono-amine oxidase-A (MAO-A) inhibitors. In vitro and ex vivo studies have demonstrated that befloxatone is a potent, reversible and competitive MAO-A inhibitor with potential antidepressant properties. Befloxatone (1) was labelled with carbon-11 (t 1=2 : 20.4 min) using [ 11 C]phosgene as reagent. Typically, starting from a 1.2 Ci (44.4 GBq) cyclotron-produced [ 11 C]CH 4 batch, 150-300 mCi (5.55-11.10 GBq) of [ 11 C]befloxatone ([ 11 C]-1) with a radiochemical-and chemical purity of more than 99% were routinely obtained within 20 min of radiosynthesis (including HPLC purification) with specific radioactivities of 500-2000 mCi/mmol (18.5-74.0 GBq/mmol). The results obtained in vivo with carbon-11-labelled befloxatone not only confirm the biochemical and pharmacological profile of befloxatone found in rodent and in human tissues but also point out [ 11 C]befloxatone as an excellent tool for the assessment of MAO-A binding sites using positron emission tomography, a high-resolution, sensitive, non-invasive and quantitative imaging technique. #
European Journal of Medicinal Chemistry, 1997
Different families of heterocycles containing 2 to 4 nitrogen atoms (oxadiazolones, tetrazoles an... more Different families of heterocycles containing 2 to 4 nitrogen atoms (oxadiazolones, tetrazoles and oxadiazinone derivatives, so-called diazoheterocyclics) are currently used as lead compounds for the design of reversible and selective monoamine oxidase B ( MAO-B) inhibitors. In order to clarify the mechanism of interaction of these molecules with the enzyme, we adopted a theoretical approach (ab initio calculations) and studied several structural and electronic properties of prototype molecules of the aryl diazo heterocyclic chemical series. This work provides a theoretical basis for structure-inhibition relationships in chemical series with potential IMAO-B properties.
Cheminform, 2010
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was e... more ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.