Papers by Hervé Schaffhauser
![Research paper thumbnail of Discovery of 7-arylsulfonyl-1,2,3,4, 4a,9a-hexahydro-benzo[4,5]furo[2,3-c]pyridines: Identification of a potent and selective 5-HT6 receptor antagonist showing activity in rat social recognition test](https://a.academia-assets.com/images/blank-paper.jpg)
Bioorganic & Medicinal Chemistry Letters, Feb 1, 2012
Serotoninergic neurotransmission has been implicated in modulation of learning and memory. It has... more Serotoninergic neurotransmission has been implicated in modulation of learning and memory. It has been demonstrated that 5-hydroxytryptamine(6) (5-HT(6)) receptor antagonists show beneficial effect on cognition in several animal models. Based on a pharmacophore model reported in the literature, we have designed and successfully identified a 7-benzenesulfonyl-1,2,3,4-tetrahydro-benzo[4,5]furo[2,3-c]pyridine (3a) scaffold as a novel class of 5-HT(6) receptor antagonists. Despite good activity against 5-HT(6) receptor, 3a exhibited poor liver microsome stability in mouse, rat and dog. It was demonstrated that the saturation of the double bond of the tetrahydropyridine ring of 3a enhanced metabolic stability. However the resulting compound, 4a (7-phenylsulfonyl-1,2,3,4,4a,9a-hexahydro-benzo[4,5]furo[2,3-c] pyridine-HCl salt) exhibited ∼30-fold loss in potency along with introduction of two chiral centers. In our optimization process for this series, we found that substituents at the 2 or 3 positions on the distal aryl group are important for enhancing activity against 5-HT(6). Separation of enantiomers and subsequent optimization and SAR with bis substituted phenyl sulfone provided potent 5-HT(6) antagonists with improved PK profiles in rat. A potent, selective 5-HT(6)R antagonist (15k) was identified from this study which showed good oral bioavailability (F=39%) in rat with brain penetration (B/P=2.76) and in vivo activity in a rat social recognition test.
European Journal of Pharmacology, Sep 1, 1997
Biochemical Pharmacology, Aug 1, 2007
In recent years, the concept of allosteric modulation of G-protein-coupled receptors (GPCRs) has ... more In recent years, the concept of allosteric modulation of G-protein-coupled receptors (GPCRs) has matured and now represents an increasingly viable approach to drug discovery. This is evident in the fact that allosteric modulators have been reported for every class of GPCR, and several are currently in clinical trials with one drug example approved and launched. The allosteric approach has been highlighted for the potential of identifying highly selective compounds with a minimal propensity to produce adverse effect. While much has been written regarding the promises of this approach, important challenges, caveats, and pitfalls exist that are often overlooked. Therefore, a balanced overview of the field that describes both the promises and the challenges of discovering allosteric modulators of GPCRs as novel drugs is presented.
Current drug targets, Jun 1, 2002
Schizophrenia is a debilitating chronic psychiatric illness affecting 1% of the population. The c... more Schizophrenia is a debilitating chronic psychiatric illness affecting 1% of the population. The cardinal features of schizophrenia are positive symptoms (thought disorder, hallucinations, catatonic behavior), negative symptoms (social withdrawal, anhedonia, apathy) and cognitive impairment. Although progress in elucidating the aetiology of schizophrenia has been slow, new insights on the neurochemical and neurophysiological mechanisms underlying the pathophysiology of this illness are beginning to emerge. The glutamate/N-methyl-D-aspartate (NMDA) hypofunction hypothesis of schizophrenia is supported by observations that administration of NMDA glutamate receptor antagonists such as phencyclidine (PCP) or ketamine induces psychosis in humans; moreover, decreased levels of glutamate and changes in several markers of glutamatergic function occur in schizophrenic brain. Administration of PCP or ketamine to rodents elicits an increase in locomotion and stereotypy accompanied by an increase in glutamate efflux in several brain regions. Systemic administration of group II metabotropic glutamate (mGlu) receptor agonists suppresses PCP-induced behavioral effects and the increase in glutamate efflux. Activation of group II mGlu receptors (mGlu2 and mGlu3) decreases glutamate release from presynaptic nerve terminals, suggesting that group II mGlu receptor agonists may be beneficial in the treatment of schizophrenia. In addition, pharmacological manipulations that enhance NMDA function may be efficacious antipsychotics. Selective activation of mGlu5 receptors significantly potentiates NMDA-induced responses, supporting this novel approach for the treatment of schizophrenia. The glutamate hypothesis of schizophrenia predicts that agents that restore the balance in glutamatergic neurotransmission will ameliorate the symptomatology associated with this illness. Development of potent, efficacious, systemically active drugs will help to address the antipsychotic potential of these novel therapeutics. This review will discuss recent progress in elucidating the pharmacology and function of group II mGlu and mGlu5 receptors in the context of current hypotheses on the pathophysiology of schizophrenia and the need for new and better antipsychotics.
Neuroscience, Dec 1, 2009
The 5-HT 6 receptor is predominantly expressed in the CNS and has been implicated in the regulati... more The 5-HT 6 receptor is predominantly expressed in the CNS and has been implicated in the regulation of cognitive function. Antagonists of the 5-HT 6 receptor improve cognitive performance in a number of preclinical models and have recently been found to be effective in Alzheimer's disease patients. Systemic administration of 5-HT 6 antagonists increases the release of acetylcholine and glutamate in the frontal cortex and dorsal hippocampus. In contrast, the selective 5-HT 6 agonist, WAY-181187, can elicit robust increases in extracellular levels of GABA. The reported behavioral and neurochemical effects of 5-HT 6 receptor ligands raise the possibility that the 5-HT 6 receptor may modulate synaptic plasticity in the hippocampus. In the present study, selective pharmacological tools were employed to determine the effect of 5-HT 6 receptor activation on long-term potentiation (LTP) in brain slices containing area CA1 of the hippocampus. While having no effect on baseline synaptic transmission, the results demonstrate that the selective 5-HT 6 agonist, WAY-181187, attenuated LTP over a narrow dose range (100-300 nM). The increase in the slope of the field excitatory post synaptic potential (fEPSP) caused by theta burst stimulation in brain slices treated with the most efficacious dose of WAY-181187 (200 nM) was 80.1؎4.0% of that observed in controls. This effect was dose-dependently blocked by the selective 5-HT 6 antagonist, SB-399885. WAY-181187 also increased the frequency of spontaneous GABA release in area CA1. As assessed by measuring and evaluating spontaneous inhibitory postsynaptic currents (sIPSCs), 200 nM WAY-181187 increased sIPSC frequency by 3.4؎0.9 Hz. This increase in GABA sIPSCs was prevented by the selective 5-HT 6 antagonist SB-399885 (300 nM). Taken together, these results suggest that the 5-HT 6 receptor plays a role in the modulation of synaptic plasticity in hippocampal area CA1 and that the regulation of GABAergic interneuron activity may underlie the cognition enhancing effects of 5-HT 6 antagonists.
Bioorganic & Medicinal Chemistry Letters, Dec 15, 2017
Positive modulation of the muscarinic M1-receptor has for a long time attracted scientists and dr... more Positive modulation of the muscarinic M1-receptor has for a long time attracted scientists and drug developers for the potential treatment of Alzheimer's disease or Schizophrenia. The precognitive potential of M1 activation has however not been clinically demonstrated as a result of side effects associated both with agonists and positive allosteric modulators (PAM's) of the M1-receptor. To avoid excessive activation of the M1-receptor we have designed a new screening format and developed the first low-shift positive allosteric modulators for the M1 receptor. Low-shift PAM's offer the potential of "use-dependent" attenuation of transmittersignaling while avoiding pseudo-agonistic behavior in vivo as a common limitation of the so far described high-shift PAM's. With these novel M1-PAM's, the M1 receptor is potentially the first GPCR for which both, high-and low shift PAM's have become available.
British Journal of Pharmacology, Jul 1, 1997
The eects of selective agonists at group I, II and III metabotropic glutamate receptors (mGluRs) ... more The eects of selective agonists at group I, II and III metabotropic glutamate receptors (mGluRs) on adenosine A 2 receptor-mediated cyclic AMP formation were compared in cross-chopped slices of adult and neonatal (8 days old) rat striatum, in the presence of 1 u ml 71 adenosine deaminase. 2 The group II selective agonist, (2S,1R,2R,3R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV), elicited a potentiation of 5'-N-ethylcarboxamidoadenosine (NECA)-stimulated cyclic AMP production with similar potencies in adult (EC 50 value 122+35 nM) and neonatal (EC 50 value 285+6 nM) brain. In contrast, the group I selective agonist (S)-dihydroxyphenylglycine ((S)-DHPG) augmented the NECA cyclic AMP response in neonatal striatum (EC 50 value 9+1 mM), but at a concentration of 100 mM, (S)-DHPG failed to aect the NECA response in adult striatal slices. 3 The potentiation evoked by (S)-DHPG was speci®c for group I mGluRs as (2S,3S,4S,)-2-methyl-2-(carboxycyclopropyl)glycine (MCCG), a group II antagonist, was ineective on the (S)-DHPG (100 mM) response at a concentration (500 mM) which reversed a similar augmentation elicited by DCG-IV (300 nM). Furthermore, a protein kinase C inhibitor (Ro 31-8220, 10 mM) markedly reversed the eect of (S)-DHPG without aecting the response to DCG-IV. 4 The mGluR agonist (2S,3S,4S,)-a-(carboxycyclopropyl)glycine (L-CCG-I), elicited a greater potentiation of NECA-stimulated cyclic AMP production in neonatal striatum in comparison with that observed in adult rat brain. Moreover, EC 50 values obtained from adult and neonatal striatum were 2+1 mM and 9+1 mM, respectively. These dierences in potency might re¯ect co-activation of both group I and group II mGluRs by L-CCG-I in neonatal striatum. 5 Distinct patterns of mGluR expression in various brain areas might account for previous con¯icting data on the nature of the mGluR able to evoke such potentiated responses.
Molecular Pharmacology, Sep 18, 2003
In the present study, we describe the characterization of a positive allosteric modulator at meta... more In the present study, we describe the characterization of a positive allosteric modulator at metabotropic glutamate subtype 2 receptors (mGluR2). N-(4-(2-Methoxyphenoxy)-phenyl-N-(2,2,2-trifluoroethylsulfonyl)-pyrid-3-ylmethylamine (LY487379) is a selective positive allosteric modulator at human mGluR2 and is without activity at human mGluR3. Furthermore, LY487379 has no intrinsic agonist or antagonist activity at hmGluR2, as determined by functional guanosine 5Ј(␥-[ 35 S]thio)triphosphate ([ 35 S]GTP␥S) binding, single-cell Ca 2ϩ imaging, and electrophysiological studies. However, LY487379 markedly potentiated glutamate-stimulated [ 35 S]GTP␥S binding in a concentration-dependent manner at hmGluR2, shifting the glutamate dose-response curve leftward by 3-fold and increasing the maximum levels of [ 35 S]GTP␥S stimulation. This effect of LY487479 was also observed to a greater extent on
![Research paper thumbnail of In vitro binding characteristics of a new selective group II metabotropic glutamate receptor radioligand, [3H]LY354740, in rat brain](https://attachments.academia-assets.com/109451190/thumbnails/1.jpg)
Molecular Pharmacology, Feb 1, 1998
The in vitro binding of [ 3 H]LY354740, the first high affinity group II-selective metabotropic g... more The in vitro binding of [ 3 H]LY354740, the first high affinity group II-selective metabotropic glutamate (mGlu) receptor radioligand, was characterized in rat cortical, hippocampal, and thalamic membranes as well as in rat brain sections. [ 3 H]LY354740 binding was saturable in all regions investigated. Nonspecific binding (in the presence of 10 M DCG-IV) was Ϸ8% of the total. Ionotropic glutamate receptor agonists, N-methyl-Daspartate, (R,S)-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate, a Na ϩ-dependent glutamate uptake blocker as well as a group I-selective mGlu receptor agonist (all up to 1 mM) did not inhibit [ 3 H]LY354740 binding to cortical membranes. However, several known metabotropic receptor ligands inhibited the binding with the following rank order of potency: LY354740 ϭ LY341495 Ͼ (2S,2ЈR,3ЈR)-2-(2Ј,3Јdicarboxycyclopropyl)glycine ϭ (2S,1ЈS,2ЈS)-2-(2-carboxycyclopropyl)glycine Ͼ glutamate ϭ (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid Ͼ (2S,1ЈS,2ЈS)-2-methyl-2-(2carboxycyclopropyl)-glycine Ͼ quisqualate Ͼ ibotenate Ͼ L-2-amino-3-phosphonopropionic acid ϭ (S)-␣-methyl-4carboxyphenylglycine Ͼ L-(ϩ)-2-amino-4-phosphonobutyric acid. N-Acetyl-aspartyl-glutamate, (2S)-␣-ethylglutamic acid, and (R,S)-␣-methyl-4-phosphonophenylglycine inhibited [ 3 H]LY354740 binding in a biphasic manner. Guanosine-5Ј-O-(3-thiotriphosphate concentration-dependently and almost completely inhibited the binding. Finally, in parasagittal sections of rat brain, a high density of specific binding was observed in the accessory olfactory bulb, cortical regions (layers 1-3 Ͼ 4-6), caudate putamen, molecular layers of the hippocampus and dentate gyrus, presubiculum, retrosplenial cortex, anteroventral thalamic nuclei, and cerebellar granular layer, reflecting its preferential (perhaps not exclusive) affinity for presynaptic and postsynaptic mGlu2 receptors. Thus, the pharmacology, tissue distribution, and sensitivity to guanosine-5Ј-O-(3-thiotriphosphate show that [ 3 H]LY354740 binding probably occurs to group II mGlu receptors in rat brain.
Neuropharmacology, Jun 1, 1996
Current Topics in Medicinal Chemistry, Feb 1, 2010
Cognitive impairment (CI) has been recognized as a core feature of Alzheimer's disease (AD) and s... more Cognitive impairment (CI) has been recognized as a core feature of Alzheimer's disease (AD) and schizophrenia. The 5-HT 6 receptor is an attractive target for the development of cognitive enhancers due to its unique localization and pharmacology. 5-HT 6 receptor antagonists have been shown to modulate multiple neurotransmitter systems and therefore enhance cognition in preclinical studies. This premise translated into the clinical efficacy of the 5-HT 6 receptor antagonist SB-742457 in mild-to-moderate AD patients. Advances in the understanding of the structureactivity-relationship, the design of novel 5-HT 6 receptor ligands and their potential application for the treatment of CI are reviewed.
Schizophrenia Research, 2012
Journal of Pharmacology and Experimental Therapeutics, 2004
List of non-standard abbreviations: 4C3HPG, 4-carboxy,3-hydroxyphenylglcyine; CHPG, (R,S)-2-chlor... more List of non-standard abbreviations: 4C3HPG, 4-carboxy,3-hydroxyphenylglcyine; CHPG, (R,S)-2-chloro-5-hydroxyphenylglycine; CPCCOEt, 7-(hydroxylimino) cyclopropa[b]chromen-1a-carboxamide ethyl ester; CPPHA, N-{4-chloro-2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl] phenyl}-2-hydroxybenzamide, DFB, 3,3'-This article has not been copyedited and formatted. The final version may differ from this version.
Current Drug Target -CNS & Neurological Disorders, 2002
Schizophrenia is a debilitating chronic psychiatric illness affecting 1% of the population. The c... more Schizophrenia is a debilitating chronic psychiatric illness affecting 1% of the population. The cardinal features of schizophrenia are positive symptoms (thought disorder, hallucinations, catatonic behavior), negative symptoms (social withdrawal, anhedonia, apathy) and cognitive impairment. Although progress in elucidating the aetiology of schizophrenia has been slow, new insights on the neurochemical and neurophysiological mechanisms underlying the pathophysiology of this illness are beginning to emerge. The glutamate/N-methyl-D-aspartate (NMDA) hypofunction hypothesis of schizophrenia is supported by observations that administration of NMDA glutamate receptor antagonists such as phencyclidine (PCP) or ketamine induces psychosis in humans; moreover, decreased levels of glutamate and changes in several markers of glutamatergic function occur in schizophrenic brain. Administration of PCP or ketamine to rodents elicits an increase in locomotion and stereotypy accompanied by an increase in glutamate efflux in several brain regions. Systemic administration of group II metabotropic glutamate (mGlu) receptor agonists suppresses PCP-induced behavioral effects and the increase in glutamate efflux. Activation of group II mGlu receptors (mGlu2 and mGlu3) decreases glutamate release from presynaptic nerve terminals, suggesting that group II mGlu receptor agonists may be beneficial in the treatment of schizophrenia. In addition, pharmacological manipulations that enhance NMDA function may be efficacious antipsychotics. Selective activation of mGlu5 receptors significantly potentiates NMDA-induced responses, supporting this novel approach for the treatment of schizophrenia. The glutamate hypothesis of schizophrenia predicts that agents that restore the balance in glutamatergic neurotransmission will ameliorate the symptomatology associated with this illness. Development of potent, efficacious, systemically active drugs will help to address the antipsychotic potential of these novel therapeutics. This review will discuss recent progress in elucidating the pharmacology and function of group II mGlu and mGlu5 receptors in the context of current hypotheses on the pathophysiology of schizophrenia and the need for new and better antipsychotics.
British Journal of Pharmacology, 1997
The eects of selective agonists at group I, II and III metabotropic glutamate receptors (mGluRs) ... more The eects of selective agonists at group I, II and III metabotropic glutamate receptors (mGluRs) on adenosine A 2 receptor-mediated cyclic AMP formation were compared in cross-chopped slices of adult and neonatal (8 days old) rat striatum, in the presence of 1 u ml 71 adenosine deaminase. 2 The group II selective agonist, (2S,1R,2R,3R)-2-(2,3-dicarboxycyclopropyl)glycine (DCG-IV), elicited a potentiation of 5'-N-ethylcarboxamidoadenosine (NECA)-stimulated cyclic AMP production with similar potencies in adult (EC 50 value 122+35 nM) and neonatal (EC 50 value 285+6 nM) brain. In contrast, the group I selective agonist (S)-dihydroxyphenylglycine ((S)-DHPG) augmented the NECA cyclic AMP response in neonatal striatum (EC 50 value 9+1 mM), but at a concentration of 100 mM, (S)-DHPG failed to aect the NECA response in adult striatal slices. 3 The potentiation evoked by (S)-DHPG was speci®c for group I mGluRs as (2S,3S,4S,)-2-methyl-2-(carboxycyclopropyl)glycine (MCCG), a group II antagonist, was ineective on the (S)-DHPG (100 mM) response at a concentration (500 mM) which reversed a similar augmentation elicited by DCG-IV (300 nM). Furthermore, a protein kinase C inhibitor (Ro 31-8220, 10 mM) markedly reversed the eect of (S)-DHPG without aecting the response to DCG-IV. 4 The mGluR agonist (2S,3S,4S,)-a-(carboxycyclopropyl)glycine (L-CCG-I), elicited a greater potentiation of NECA-stimulated cyclic AMP production in neonatal striatum in comparison with that observed in adult rat brain. Moreover, EC 50 values obtained from adult and neonatal striatum were 2+1 mM and 9+1 mM, respectively. These dierences in potency might re¯ect co-activation of both group I and group II mGluRs by L-CCG-I in neonatal striatum. 5 Distinct patterns of mGluR expression in various brain areas might account for previous con¯icting data on the nature of the mGluR able to evoke such potentiated responses.
Brain Research, 2008
The receptor localization of metabotropic glutamate receptors (mGlu) 2 and 3 was examined by usin... more The receptor localization of metabotropic glutamate receptors (mGlu) 2 and 3 was examined by using in situ hybridization and a well-characterized mGlu2-selective antibody in the rat forebrain. mGlu2 was highly and discretely expressed in cell bodies in almost all of the key regions of the limbic system in the forebrain, including the midline and intralaminar structures of the thalamus, the association cortices, the dentate gyrus of the hippocampus, the medial mammillary nucleus, and the lateral and basolateral nuclei of the amygdala. Moreover, presynaptic mGlu2 terminals were found in most of the forebrain structures, especially in the lateral part of the central nucleus of the amygdala, and the CA1 region of the hippocampus. Although some overlaps exist, such as in the hippocampus and the amygdala, the expression of mGlu3 mRNA, however, appeared to be more disperse, compared with that of mGlu2 mRNA. These distribution results support previous behavioral studies that the mGlu2 and 3 receptors may play important roles in emotional responses. In addition to its expression in glia, mGlu3 was distinctively expressed in cells in the GABAergic reticular nucleus of the thalamus. Local infusion of a non-selective mGlu2/3 agonist, LY379268, in the reticular nucleus of the thalamus, significantly reduced GABA release, suggesting that mGlu3 may also play a role in central disinhibition.
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Papers by Hervé Schaffhauser