Mammalian RF-amide peptides including RF-amide-related peptides-1 and -3, neuropeptides AF and FF... more Mammalian RF-amide peptides including RF-amide-related peptides-1 and -3, neuropeptides AF and FF, Prolactin releasing peptides, Kisspeptins and RFa peptides are currently considered endogenous peptides for the GPCRs NPFF1R, NPFF2R, GPR10, GPR54 and GPR103, respectively. While NPFF1R and NPFF2R displayed high affinity for all the RF-amide peptides, GPR10, GPR54 and GPR103 only bind their cognate ligands. Through a systematic and sequential N-terminus deletion and benzoylation of either RF-amide neuropeptide (RFRP-3, NPFF, Kp-10, PrRP20, and 26RFa), we report the corresponding impact on affinity and activity towards all the RF-amide receptors (NPFF1R, NPFF2R, GPR10, GPR54 and GPR103). Our results highlight the difficulty to develop selective peptide ligands for GPR10, GPR54 or GPR103 without a modification of the C-terminus RF-amide signature, but open the door to the design of new RF-amide peptides acting as agonist for one receptor and antagonist for another one.
ABSTRACT A new two step strategy for the preparation of 1,4-benzodiazepin-2-ones has been develop... more ABSTRACT A new two step strategy for the preparation of 1,4-benzodiazepin-2-ones has been developed starting from the 2-halogenobenzophenone under Buchwald conditions (Pd(OAc)2, XantPhos, Cs2CO3, dioxane 100 °C). This strategy has been extended to two 2-halogeno-3-benzoyl-azines (pyridines, pyridazines).
We report a selective ruthenium catalyzed reduction of tertiary amides on the side chain of Fmoc-... more We report a selective ruthenium catalyzed reduction of tertiary amides on the side chain of Fmoc-Gln-OtBu derivatives, leading to innovative unnatural α,β or γ-amino acids functionalized with tertiary amines. Rapid and scalable, this process allowed us to build a library of basic unnatural amino acids at the gram-scale and directly usable for liquid- or solid-phase peptide synthesis. The diversity of available tertiary amines allows us to modulate the physicochemical properties of the resulting amino acids, such as basicity or hydrophobicity.
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 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.
Ligand-gated ion channels (LGICs) are considered as attractive protein targets in the search for ... more Ligand-gated ion channels (LGICs) are considered as attractive protein targets in the search for new therapeutic agents. Nowadays, this strategy involves the capability to screen large chemical libraries. We present a new Tag-lite ligand binding assay targeting LGICs on living cells. This technology combines the use of suicide enzyme tags fused to channels of interest with homogeneous time-resolved fluorescence (HTRF) as the detection readout. Using the 5-HT3 receptor as system model, we showed that the pharmacology of the HALO-5HT3 receptor was identical to that of the native receptor. After validation of the assay by using 5-HT3 agonists and antagonists of reference, a pilot screen enabled us to identify azelastine, a well-known histamine H1 antagonist, as a potent 5-HT3 antagonist. This interesting result was confirmed with electrophysiological experiments. The method described here is easy to implement and could be applicable for other LGICs, opening new ways for the screening of chemical libraries.
Neuropeptide Y (NPY) is a well established anticonvulsant and first-in-class antiepileptic neurop... more Neuropeptide Y (NPY) is a well established anticonvulsant and first-in-class antiepileptic neuropeptide. In this study, the controversial role of NPY1 receptors in epilepsy was reassessed by testing two highly selective NPY1 receptor ligands and a mixed NPY1/NPFF receptor antagonist BIBP3226 in a rat model for limbic seizures. While BIBP3226 significantly attenuated the pilocarpine-induced seizures, neither of the highly selective NPY1 receptor ligands altered the seizure severity. Administration of the NPFF1/NPFF2 receptor antagonist RF9 also significantly attenuated limbic seizure activity. To further prove the involvement of NPFF receptors in these seizure-modulating effects, low and high affinity antagonists for the NPFF receptors were tested. We observed that the low affinity ligand failed to exhibit anticonvulsant properties while the two high affinity ligands significantly attenuated the seizures. Continuous NPFF1 receptor agonist administration also inhibited limbic seizures whereas bolus administration of the NPFF1 receptor agonist was without effect. This suggests that continuous agonist perfusion could result in NPFF1 receptor desensitization and mimic NPFF1 receptor antagonist administration. Our data unveil for the first time the involvement of the NPFF system in the management of limbic seizures.
ABSTRACT The in plane critical current density jc (B, Θ, T) of dc-sputtered YBa2Cu3O7-films and Y... more ABSTRACT The in plane critical current density jc (B, Θ, T) of dc-sputtered YBa2Cu3O7-films and YBa2Cu3O7/PrBa2Cu3O7-superlattices was measured in dependence of the angle Θ between the magnetic field and the -axis of the films in two orientations: 1. The current direction is parallel to the axis of rotation (i.e. always). 2. The current flows perpendicular to the axis of rotation (i. e. ). For low temperatures we do not find any difference between the two current orientations, and the critical current density behaves like jc (B cos Θ, 0°). For higher temperatures the two cases differ from each other for Θ near to the maxima in jc at 90° and 270° for the YBa2Cu3O7-films whereas for YBa2Cu3O7/PrBa2Cu3O7-superlattices we hardly find any change for both experimental setups. We compare the behaviour of the experimental results for the two orientations for the YBa2Cu3O7-films and YBa2Cu3O7/PrBa2Cu3O7-superlattices and discuss the temperature dependence of the intrinsic pinning force density.
ABSTRACT Superconductivity in high-Tc oxides originates from the presence of (CuO2)-planes which ... more ABSTRACT Superconductivity in high-Tc oxides originates from the presence of (CuO2)-planes which lead to highly anisotropic normal and superconducting transport properties. The short coherence length ξc ≈ 1 to 3Å causes a spatial variation of the order parameter along the c-direction with dramatic consequences on the vortex dynamics. As model systems to study the influence of structural changes we prepared epitaxial YBa2(Cu1−xTMx)3O7 films (TM = Zn and Ni), Bi2Sr2CaCu2O8 films and coherent YBa2Cu3O7/PrBa2Cu3O7 superlattices. Measurements of the critical current density clearly reveal the intrinsic pinning mechanism in YBa2Cu3O7 for B ⊥ c at low temperatures which disappears approaching Tc. Small transition metal dopings act as pinning centers reducing dissipation due to thermally activated flux movement. The decoupling of the (CuO2)-layers in the superlattices causes a transition from anisotropic 3d to 2d behavior. Therefore the superconducting properties in external magnetic fields, which resemble closely those of Bi2Sr2CaCu2O8 films, are dominated by the field component parallel to the c-axis. For B⊥ c the resistive transitions ρ (B, T) and the critical current density jc (B, T) are nearly field independent.
La présente invention concerne des composés dérivés de quinoléine et de quinoxaline, leur prépara... more La présente invention concerne des composés dérivés de quinoléine et de quinoxaline, leur préparation et leurs utilisations, notamment dans le domaine thérapeutique, vaccinal ou pour le développement de composés actifs. Les composés de l'invention répondent généralement à la formule (I), et leurs sels pharmaceutiquement acceptables.
A previous study around adenine nucleotides afforded the reference N(6)-methyl-2&... more A previous study around adenine nucleotides afforded the reference N(6)-methyl-2'-deoxyadenosine-3',5'-bisphosphate (1a, MRS 2179) as a selective human P2Y(1) receptor antagonist (pA(2)=6.55+/-0.05) with antithrombotic properties. In the present paper, we have synthesized and tested in vitro various 2-substituted derivatives with the goal of exploring the 2-position binding region and developing more potent P2Y(1) receptor antagonists. Thus, we have adopted a novel and versatile chemical pathway using a palladium-catalyzed cross-coupling reaction with the 2-iodinated derivative 7 as a common intermediate for a very efficient synthesis of the 2-alkyl-N(6)-methyl-2'-deoxyadenosine-3',5'-bisphosphate nucleotides 1e-i. The biological activity was evaluated through the ability of compounds to inhibit ADP-induced platelet aggregation, intracellular calcium rise and to displace the specific binding of [(33)P]2-MeSADP. 2-Ethyl and 2-propyl groups appeared to be tolerated, whereas a bulky group or a C(3) linear substituent dramatically decreased potency of antagonists. The 2-ethynyl derivative 1h (pA(2)=7.54+/-0.10) was significantly more potent (10-fold) as an antagonist when compared to the reference 1a, revealing a potential electronic interaction highly favorable between triple bond orbitals and the P2Y(1) receptor at this position.
ABSTRACT Because of their large spectrum of applications, poly-functionalized pyridines remain an... more ABSTRACT Because of their large spectrum of applications, poly-functionalized pyridines remain an attractive challenge in modern organic chemistry. We describe the poly-functionalization of halopyridines through a series of sequential and regioselective palladium-catalyzed cross-coupling reactions (Suzuki–Miyaura, Sonogashira and Buchwald–Hartwig reactions). This strategy was applied to the synthesis of several analogs of single non-peptidic known GPR54 antagonists.
Guanabenz (GA) is an orally active α2-adrenergic agonist that has been used for many years for th... more Guanabenz (GA) is an orally active α2-adrenergic agonist that has been used for many years for the treatment of hypertension. We recently described that GA is also active against both yeast and mammalian prions in an α2-adrenergic receptor-independent manner. These data suggest that this side-activity of GA could be explored for the treatment of prion-based diseases and other amyloid-based disorders. In this perspective, the potent antihypertensive activity of GA happens to be an annoying side-effect that could limit its use. In order to get rid of GA agonist activity at α2-adrenergic receptors, we performed a structure-activity relationship study around GA based on changes of the chlorine positions on the benzene moiety and then on the modifications of the guanidine group. Hence, we identified the two derivatives 6 and 7 that still possess a potent antiprion activity but were totally devoid of any agonist activity at α2-adrenergic receptors. Similarly to GA, 6 and 7 were also able ...
Mammalian RF-amide peptides including RF-amide-related peptides-1 and -3, neuropeptides AF and FF... more Mammalian RF-amide peptides including RF-amide-related peptides-1 and -3, neuropeptides AF and FF, Prolactin releasing peptides, Kisspeptins and RFa peptides are currently considered endogenous peptides for the GPCRs NPFF1R, NPFF2R, GPR10, GPR54 and GPR103, respectively. While NPFF1R and NPFF2R displayed high affinity for all the RF-amide peptides, GPR10, GPR54 and GPR103 only bind their cognate ligands. Through a systematic and sequential N-terminus deletion and benzoylation of either RF-amide neuropeptide (RFRP-3, NPFF, Kp-10, PrRP20, and 26RFa), we report the corresponding impact on affinity and activity towards all the RF-amide receptors (NPFF1R, NPFF2R, GPR10, GPR54 and GPR103). Our results highlight the difficulty to develop selective peptide ligands for GPR10, GPR54 or GPR103 without a modification of the C-terminus RF-amide signature, but open the door to the design of new RF-amide peptides acting as agonist for one receptor and antagonist for another one.
ABSTRACT A new two step strategy for the preparation of 1,4-benzodiazepin-2-ones has been develop... more ABSTRACT A new two step strategy for the preparation of 1,4-benzodiazepin-2-ones has been developed starting from the 2-halogenobenzophenone under Buchwald conditions (Pd(OAc)2, XantPhos, Cs2CO3, dioxane 100 °C). This strategy has been extended to two 2-halogeno-3-benzoyl-azines (pyridines, pyridazines).
We report a selective ruthenium catalyzed reduction of tertiary amides on the side chain of Fmoc-... more We report a selective ruthenium catalyzed reduction of tertiary amides on the side chain of Fmoc-Gln-OtBu derivatives, leading to innovative unnatural α,β or γ-amino acids functionalized with tertiary amines. Rapid and scalable, this process allowed us to build a library of basic unnatural amino acids at the gram-scale and directly usable for liquid- or solid-phase peptide synthesis. The diversity of available tertiary amines allows us to modulate the physicochemical properties of the resulting amino acids, such as basicity or hydrophobicity.
ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance t... more ABSTRACT ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 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.
Ligand-gated ion channels (LGICs) are considered as attractive protein targets in the search for ... more Ligand-gated ion channels (LGICs) are considered as attractive protein targets in the search for new therapeutic agents. Nowadays, this strategy involves the capability to screen large chemical libraries. We present a new Tag-lite ligand binding assay targeting LGICs on living cells. This technology combines the use of suicide enzyme tags fused to channels of interest with homogeneous time-resolved fluorescence (HTRF) as the detection readout. Using the 5-HT3 receptor as system model, we showed that the pharmacology of the HALO-5HT3 receptor was identical to that of the native receptor. After validation of the assay by using 5-HT3 agonists and antagonists of reference, a pilot screen enabled us to identify azelastine, a well-known histamine H1 antagonist, as a potent 5-HT3 antagonist. This interesting result was confirmed with electrophysiological experiments. The method described here is easy to implement and could be applicable for other LGICs, opening new ways for the screening of chemical libraries.
Neuropeptide Y (NPY) is a well established anticonvulsant and first-in-class antiepileptic neurop... more Neuropeptide Y (NPY) is a well established anticonvulsant and first-in-class antiepileptic neuropeptide. In this study, the controversial role of NPY1 receptors in epilepsy was reassessed by testing two highly selective NPY1 receptor ligands and a mixed NPY1/NPFF receptor antagonist BIBP3226 in a rat model for limbic seizures. While BIBP3226 significantly attenuated the pilocarpine-induced seizures, neither of the highly selective NPY1 receptor ligands altered the seizure severity. Administration of the NPFF1/NPFF2 receptor antagonist RF9 also significantly attenuated limbic seizure activity. To further prove the involvement of NPFF receptors in these seizure-modulating effects, low and high affinity antagonists for the NPFF receptors were tested. We observed that the low affinity ligand failed to exhibit anticonvulsant properties while the two high affinity ligands significantly attenuated the seizures. Continuous NPFF1 receptor agonist administration also inhibited limbic seizures whereas bolus administration of the NPFF1 receptor agonist was without effect. This suggests that continuous agonist perfusion could result in NPFF1 receptor desensitization and mimic NPFF1 receptor antagonist administration. Our data unveil for the first time the involvement of the NPFF system in the management of limbic seizures.
ABSTRACT The in plane critical current density jc (B, Θ, T) of dc-sputtered YBa2Cu3O7-films and Y... more ABSTRACT The in plane critical current density jc (B, Θ, T) of dc-sputtered YBa2Cu3O7-films and YBa2Cu3O7/PrBa2Cu3O7-superlattices was measured in dependence of the angle Θ between the magnetic field and the -axis of the films in two orientations: 1. The current direction is parallel to the axis of rotation (i.e. always). 2. The current flows perpendicular to the axis of rotation (i. e. ). For low temperatures we do not find any difference between the two current orientations, and the critical current density behaves like jc (B cos Θ, 0°). For higher temperatures the two cases differ from each other for Θ near to the maxima in jc at 90° and 270° for the YBa2Cu3O7-films whereas for YBa2Cu3O7/PrBa2Cu3O7-superlattices we hardly find any change for both experimental setups. We compare the behaviour of the experimental results for the two orientations for the YBa2Cu3O7-films and YBa2Cu3O7/PrBa2Cu3O7-superlattices and discuss the temperature dependence of the intrinsic pinning force density.
ABSTRACT Superconductivity in high-Tc oxides originates from the presence of (CuO2)-planes which ... more ABSTRACT Superconductivity in high-Tc oxides originates from the presence of (CuO2)-planes which lead to highly anisotropic normal and superconducting transport properties. The short coherence length ξc ≈ 1 to 3Å causes a spatial variation of the order parameter along the c-direction with dramatic consequences on the vortex dynamics. As model systems to study the influence of structural changes we prepared epitaxial YBa2(Cu1−xTMx)3O7 films (TM = Zn and Ni), Bi2Sr2CaCu2O8 films and coherent YBa2Cu3O7/PrBa2Cu3O7 superlattices. Measurements of the critical current density clearly reveal the intrinsic pinning mechanism in YBa2Cu3O7 for B ⊥ c at low temperatures which disappears approaching Tc. Small transition metal dopings act as pinning centers reducing dissipation due to thermally activated flux movement. The decoupling of the (CuO2)-layers in the superlattices causes a transition from anisotropic 3d to 2d behavior. Therefore the superconducting properties in external magnetic fields, which resemble closely those of Bi2Sr2CaCu2O8 films, are dominated by the field component parallel to the c-axis. For B⊥ c the resistive transitions ρ (B, T) and the critical current density jc (B, T) are nearly field independent.
La présente invention concerne des composés dérivés de quinoléine et de quinoxaline, leur prépara... more La présente invention concerne des composés dérivés de quinoléine et de quinoxaline, leur préparation et leurs utilisations, notamment dans le domaine thérapeutique, vaccinal ou pour le développement de composés actifs. Les composés de l'invention répondent généralement à la formule (I), et leurs sels pharmaceutiquement acceptables.
A previous study around adenine nucleotides afforded the reference N(6)-methyl-2&... more A previous study around adenine nucleotides afforded the reference N(6)-methyl-2'-deoxyadenosine-3',5'-bisphosphate (1a, MRS 2179) as a selective human P2Y(1) receptor antagonist (pA(2)=6.55+/-0.05) with antithrombotic properties. In the present paper, we have synthesized and tested in vitro various 2-substituted derivatives with the goal of exploring the 2-position binding region and developing more potent P2Y(1) receptor antagonists. Thus, we have adopted a novel and versatile chemical pathway using a palladium-catalyzed cross-coupling reaction with the 2-iodinated derivative 7 as a common intermediate for a very efficient synthesis of the 2-alkyl-N(6)-methyl-2'-deoxyadenosine-3',5'-bisphosphate nucleotides 1e-i. The biological activity was evaluated through the ability of compounds to inhibit ADP-induced platelet aggregation, intracellular calcium rise and to displace the specific binding of [(33)P]2-MeSADP. 2-Ethyl and 2-propyl groups appeared to be tolerated, whereas a bulky group or a C(3) linear substituent dramatically decreased potency of antagonists. The 2-ethynyl derivative 1h (pA(2)=7.54+/-0.10) was significantly more potent (10-fold) as an antagonist when compared to the reference 1a, revealing a potential electronic interaction highly favorable between triple bond orbitals and the P2Y(1) receptor at this position.
ABSTRACT Because of their large spectrum of applications, poly-functionalized pyridines remain an... more ABSTRACT Because of their large spectrum of applications, poly-functionalized pyridines remain an attractive challenge in modern organic chemistry. We describe the poly-functionalization of halopyridines through a series of sequential and regioselective palladium-catalyzed cross-coupling reactions (Suzuki–Miyaura, Sonogashira and Buchwald–Hartwig reactions). This strategy was applied to the synthesis of several analogs of single non-peptidic known GPR54 antagonists.
Guanabenz (GA) is an orally active α2-adrenergic agonist that has been used for many years for th... more Guanabenz (GA) is an orally active α2-adrenergic agonist that has been used for many years for the treatment of hypertension. We recently described that GA is also active against both yeast and mammalian prions in an α2-adrenergic receptor-independent manner. These data suggest that this side-activity of GA could be explored for the treatment of prion-based diseases and other amyloid-based disorders. In this perspective, the potent antihypertensive activity of GA happens to be an annoying side-effect that could limit its use. In order to get rid of GA agonist activity at α2-adrenergic receptors, we performed a structure-activity relationship study around GA based on changes of the chlorine positions on the benzene moiety and then on the modifications of the guanidine group. Hence, we identified the two derivatives 6 and 7 that still possess a potent antiprion activity but were totally devoid of any agonist activity at α2-adrenergic receptors. Similarly to GA, 6 and 7 were also able ...
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Papers by Martine Schmitt