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Michael S Malamas,
Hans Stange,
Rudolf Schindler,
Hans-Joachim Lankau,
Christian Grunwald,
Barbara Langen,
Ute Egerland,
Thorsten Hage,
Yike Ni,
James Erdei, [......],
Steve Grauer,
Julie Brennan,
Rachel Navarra,
Radka Graf,
Boyd L Harrison,
Albert Robichaud,
Thomas Kronbach,
Menelas N Pangalos,
Nicholas J Brandon,
Norbert Hoefgen
[show abstract]
[hide abstract]
ABSTRACT: The identification of highly potent and orally active triazines for the inhibition of PDE10A is reported. The new analogs exhibit low-nanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired drug-like properties. Employing structure-based drug design approaches, we investigated the selectivity of PDE10A inhibitors against other known PDE isoforms, by methodically exploring the various sub-regions of the PDE10A ligand binding pocket. A systematic assessment of the ADME and pharmacokinetic properties of the newly synthesized compounds has led to the design of drug-like candidates with good brain permeability and desirable drug kinetics (t(1/2), bioavailability, clearance). Compound 66 was highly potent for PDE10A (IC(50)=1.4 nM), demonstrated high selectivity (>200×) for the other PDEs, and was efficacious in animal models of psychoses; reversal of MK-801 induced hyperactivity (MED=0.1mg/kg) and conditioned avoidance responding (CAR; ID(50)=0.2 mg/kg).
Bioorganic & medicinal chemistry letters 07/2012; 22(18):5876-84. · 2.65 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: The 5-HT(2C) receptor is a highly complex, highly regulated receptor which is widely distributed throughout the brain. The 5-HT(2C) receptor couples to multiple signal transduction pathways leading to engagement of a number of intracellular signaling molecules. Moreover, there are multiple allelic variants of the 5-HT(2C) receptor and the receptor is subject to RNA editing in the coding regions. The complexity of this receptor is further emphasized by the studies suggesting the utility of either agonists or antagonists in the treatment of schizophrenia. While several 5-HT(2C) agonists have demonstrated clinical efficacy in obesity (lorcaserin, PRX-000933), the focus of this review is on the therapeutic potential of 5-HT(2C) agonists in schizophrenia. To this end, the preclinical profile of 5-HT(2C) agonists from a neurochemical, electrophysiological, and a behavioral perspective is indicative of antipsychotic-like efficacy without extrapyramidal symptoms or weight gain. Recently, the selective 5-HT(2C) agonist vabicaserin demonstrated clinical efficacy in a Phase II trial in schizophrenia patients without weight gain and with low EPS liability. These data are highly encouraging and suggest that 5-HT(2C) agonists are potential therapeutics for the treatment of psychiatric disorders.
Handbook of experimental pharmacology 01/2012;
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Michael S Malamas,
Yike Ni,
James Erdei,
Hans Stange,
Rudolf Schindler,
Hans-Joachim Lankau,
Christian Grunwald,
Kristi Yi Fan,
Kevin Parris,
Barbara Langen, [......],
Steve Grauer,
Julie Brennan,
Rachel Navarra,
Radka Graf,
Boyd L Harrison,
Albert Robichaud,
Thomas Kronbach,
Menelas N Pangalos,
Norbert Hoefgen,
Nicholas J Brandon
[show abstract]
[hide abstract]
ABSTRACT: The identification of highly potent and orally active phenylpyrazines for the inhibition of PDE10A is reported. The new analogues exhibit subnanomolar potency for PDE10A, demonstrate high selectivity against all other members of the PDE family, and show desired druglike properties. Employing structure-based drug design approaches, we methodically explored two key regions of the binding pocket of the PDE10A enzyme to alter the planarity of the parent compound 1 and optimize its affinity for PDE10A. Bulky substituents at the C9 position led to elimination of the mutagenicity of 1, while a crucial hydrogen bond interaction with Glu716 markedly enhanced its potency and selectivity. A systematic assessment of the ADME and PK properties of the new analogues led to druglike development candidates. One of the more potent compounds, 96, displayed an IC(50) for PDE10A of 0.7 nM and was active in predictive antipsychotic animal models.
Journal of Medicinal Chemistry 11/2011; 54(21):7621-38. · 4.80 Impact Factor
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Karen L Marquis,
Thomas A Comery,
Flora Jow,
Rachel L Navarra,
Steven M Grauer,
Claudine Pulicicchio,
Cody Kelley,
Julie A Brennan,
Renza Roncarati,
Carla Scali,
Simon Haydar,
Chiara Ghiron,
Georg C Terstappen,
John Dunlop
[show abstract]
[hide abstract]
ABSTRACT: α7 nicotinic acetylcholine receptor (nAChR) agonists are proposed as candidate agents for the adjunctive treatment of cognitive deficits associated with schizophrenia. Despite the pursuit of such an approach clinically, it is surprising that the preclinical profile of pro-cognitive agents in conjunction with antipsychotic drugs is currently unexplored.
We determined if the memory-enhancing effects of the selective α7 nAChR agonist WYE-103914 were preserved in the presence of the atypical antipsychotic drug risperidone, and if the antipsychotic-like profile of risperidone was preserved in the presence of WYE-103914.
Using the rat novel object recognition (NOR) paradigm, the maintenance of memory-enhancing activity of the α7 nAChR agonist WYE-103914 in the presence of risperidone was examined. Similarly, in the standard tests of antipsychotic-like activity, apomorphine-induced climbing (AIC) in mice and conditioned avoidance responding (CAR) in rats, the preservation of antipsychotic-like activity of risperidone was evaluated in the presence of WYE-103914.
WYE-103914 exhibited memory-enhancing activity in rat NOR, and this effect of WYE-103914 was retained in the presence of risperidone. In AIC, the atypical antipsychotic profile of risperidone was not significantly altered by WYE-103914. In contrast, WYE-103914 moderately potentiated the efficacy profile of risperidone in CAR, an effect that did not appear to be convincingly linked to a pharmacokinetic interaction.
These data underscore the value of a preclinical evaluation of the adjunctive profile of a memory-enhancing agent in combination with antipsychotics and provide further support to augmentation with α7 nAChR agonists to address the cognitive deficits associated with schizophrenia.
Psychopharmacologia 06/2011; 218(4):635-47. · 4.08 Impact Factor
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Chiara Ghiron,
Simon N Haydar,
Suzan Aschmies,
Hendrick Bothmann,
Cristiana Castaldo,
Giuseppe Cocconcelli,
Thomas A Comery,
Li Di,
John Dunlop,
Tim Lock, [......],
Joanna Quinn,
Albert J Robichaud,
Renza Roncarati,
Carla Scali,
Georg C Terstappen,
Elisa Turlizzi,
Michela Valacchi,
Maurizio Varrone,
Riccardo Zanaletti,
Ugo Zanelli
[show abstract]
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ABSTRACT: Alpha-7 nicotinic acetylcholine receptor (alpha7 nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment. We report a series of novel, potent small molecule agonists (4-18) of the alpha7 nAChR deriving from our continuing efforts in the areas of Alzheimer's disease and schizophrenia. One of the compounds of the series containing a urea moiety (16) was further shown to be a selective agonist of the alpha7 nAChR with excellent in vitro and in vivo profiles, brain penetration, and oral bioavailability and demonstrated in vivo efficacy in multiple behavioral cognition models. Structural modifications leading to the improved selectivity profile and the biological evaluation of this series of compounds are discussed.
Journal of Medicinal Chemistry 06/2010; 53(11):4379-89. · 4.80 Impact Factor
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Norbert Höfgen,
Hans Stange,
Rudolf Schindler,
Hans-Joachim Lankau,
Christian Grunwald,
Barbara Langen,
Ute Egerland,
Peter Tremmel,
Menelas N Pangalos, Karen L Marquis,
Thorsten Hage,
Boyd L Harrison,
Michael S Malamas,
Nicholas J Brandon,
Thomas Kronbach
[show abstract]
[hide abstract]
ABSTRACT: Novel imidazo[1,5-a]pyrido[3,2-e]pyrazines have been synthesized and characterized as both potent and selective phosphodiesterase 10A (PDE10A) inhibitors. For in vitro characterization, inhibition of PDE10A mediated cAMP hydrolysis was used and a QSAR model was established to analyze substitution effects. The outcome of this analysis was complemented by the crystal structure of PDE10A in complex with compound 49. Qualitatively new interactions between inhibitor and binding site were found, contrasting with previously published crystal structures of papaverine-like inhibitors. In accordance with the known antipsychotic potential of PDE10A inhibitors, MK-801 induced stereotypy and hyperactivity in rats were reversed by selected compounds. Thus, a promising compound class has been identified for the treatment of schizophrenia that could circumvent side effects connected with current therapies.
Journal of Medicinal Chemistry 06/2010; 53(11):4399-411. · 4.80 Impact Factor
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Keith J. Murphy,
Judith P. F. Ter Horst,
Andrew W. Cassidy,
Ian E. J. DeSouza,
Marina Morgunova,
Christine Li,
Laura M. Connole,
Niamh C. O’Sullivan,
Jennifer S. Loscher,
Angela T. Brady, [......],
Caitlin M. Wantuch,
Zoe A. Hughes,
Sean K. Mulvany,
Desmond G. Higgins,
Menelas N. Pangalos, Karen L. Marquis,
William T. O’Connor,
Robert H. Ring,
David Von Schack,
Ciaran M. Regan
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ABSTRACT: J. Neurochem. (2010) 113, 601–614.AbstractThe critical sequence of molecular, neurotransmission and synaptic disruptions that underpin the emergence of psychiatric disorders like schizophrenia remain to be established with progress only likely using animal models that capture key features of such disorders. We have related the emergence of behavioural, neurochemical and synapse ultrastructure deficits to transcriptional dysregulation in the medial prefrontal cortex of Wistar rats reared in isolation. Isolation reared animals developed sensorimotor deficits at postnatal day 60 which persisted into adulthood. Analysis of gene expression prior to the emergence of the sensorimotor deficits revealed a significant disruption in transcriptional control, notably of immediate early and interferon-associated genes. At postnatal day 60 many gene transcripts relating particularly to GABA transmission and synapse structure, for example Gabra4, Nsf, Syn2 and Dlgh1, transiently increased expression. A subsequent decrease in genes such as Gria2 and Dlgh2 at postnatal day 80 suggested deficits in glutamatergic transmission and synapse integrity, respectively. Microdialysis studies revealed decreased extracellular glutamate suggesting a state of hypofrontality while ultrastructural analysis showed total and perforated synapse complement in layer III to be significantly reduced in the prefrontal cortex of postnatal day 80 isolated animals. These studies provide a molecular framework to understand the developmental emergence of the structural and behavioural characteristics that may in part define psychiatric illness.
Journal of Neurochemistry 04/2010; 113(3):601 - 614. · 4.06 Impact Factor
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Yinfa Yan,
Ping Zhou,
David P Rotella,
Rolf Feenstra,
Chris G Kruse,
Jan-Hendrik Reinders,
Martina van der Neut,
Margaret Lai,
Jean Zhang,
Dianne M Kowal,
Tikva Carrick, Karen L Marquis,
Mark H Pausch,
Albert J Robichaud
[show abstract]
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ABSTRACT: A dihydroquinolinone moiety was found to be a potent serotonin reuptake inhibitor pharmacophore when combined with certain amines. This fragment was coupled with selected D(2) ligands to prepare a series of dual acting compounds with attractive in vitro profiles as dopamine D(2) partial agonists and serotonin reuptake inhibitors. Structure-activity studies revealed that the linker plays a key role in contributing to D(2) affinity, function, and SRI activity.
Bioorganic & medicinal chemistry letters 03/2010; 20(9):2983-6. · 2.65 Impact Factor
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Julie A Brennan,
Radka Graf,
Steven M Grauer,
Rachel L Navarra,
Claudine M Pulicicchio,
Zoë A Hughes,
Qian Lin,
Caitlin Wantuch,
Sharon Rosenzweig-Lipson,
Farhana Pruthi, [......],
Martina van de Neut,
Albert J Robichaud,
David Rotella,
Rolf W Feenstra,
Chris Kruse,
Pierre Broqua,
Chad E Beyer,
Andrew C McCreary,
Mark H Pausch, Karen L Marquis
[show abstract]
[hide abstract]
ABSTRACT: The preclinical characterization of WS-50030 [7-{4-[3-(1H-inden-3-yl)propyl]piperazin-1-yl}-1,3-benzoxazol-2(3H)-one] is described. In vitro binding and functional studies revealed highest affinity to the D(2) receptor (D(2L) K(i), 4.0 nM) and serotonin transporter (K(i), 7.1 nM), potent D(2) partial agonist activity (EC(50), 0.38 nM; E(max), 30%), and complete block of the serotonin transporter (IC(50), 56.4 nM). Consistent with this in vitro profile, WS-50030 (10 mg/kg/day, 21 days) significantly increased extracellular 5-HT in the rat medial prefrontal cortex, short-term WS-50030 treatment blocked apomorphine-induced climbing (ID(50), 0.51 mg/kg) in a dose range that produced minimal catalepsy in mice and induced low levels of contralateral rotation in rats with unilateral substantia nigra 6-hydroxydopamine lesions (10 mg/kg i.p.), a behavioral profile similar to that of the D(2) partial agonist aripiprazole. In a rat model predictive of antipsychotic-like activity, WS-50030 and aripiprazole reduced conditioned avoidance responding by 42 and 55% at 10 mg/kg, respectively. Despite aripiprazole's reported lack of effect on serotonin transporters, long-term treatment with aripiprazole or WS-50030 reversed olfactory bulbectomy-induced hyperactivity at doses that did not reduce activity in sham-operated rats, indicating antidepressant-like activity for both compounds. Despite possessing serotonin reuptake inhibitory activity in addition to D(2) receptor partial agonism, WS-50030 displays activity in preclinical models predictive of antipsychotic- and antidepressant efficacy similar to aripiprazole, suggesting potential efficacy of WS-50030 versus positive and negative symptoms of schizophrenia, comorbid mood symptoms, bipolar disorder, major depressive disorder, and treatment-resistant depression. Furthermore, WS-50030 provides a tool to further explore how combining these mechanisms might differentiate from other antipsychotics or antidepressants.
Journal of Pharmacology and Experimental Therapeutics 10/2009; 332(1):190-201. · 3.83 Impact Factor
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David P Rotella,
Geraldine R McFarlane,
Alexander Greenfield,
Cristina Grosanu,
Albert J Robichaud,
Rajiah Aldrin Denny,
Rolf W Feenstra,
Sara Núñez-García,
Jan-Hendrik Reinders,
Martina van der Neut, [......],
Margaret Lai,
Jean Zhang,
Dianne M Kowal,
Tikva Carrick,
Steven M Grauer,
Rachel L Navarra,
Radka Graf,
Julie Brennan, Karen L Marquis,
Mark H Pausch
[show abstract]
[hide abstract]
ABSTRACT: A 5-fluoro-tetrahydrocarbazole serotonin reuptake inhibitor (SRI) building block was combined with a variety of linkers and dopamine D2 receptor ligands in an attempt to identify potent D2 partial agonist/SRI molecules for treatment of schizophrenia. This approach has the potential to treat a broader range of symptoms compared to existing therapies. Selected compounds in this series demonstrate high affinity for both targets and D2 partial agonism in cell-based and in vivo assays.
Bioorganic & medicinal chemistry letters 09/2009; 19(19):5552-5. · 2.65 Impact Factor
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Sheree F Logue,
Steven M Grauer,
Janet Paulsen,
Radka Graf,
Noel Taylor,
M Amy Sung,
Lynn Zhang,
Zoë Hughes,
Virginia L Pulito,
Feng Liu,
Sharon Rosenzweig-Lipson,
Nicholas J Brandon, Karen L Marquis,
Brian Bates,
Mark Pausch
[show abstract]
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ABSTRACT: In rodents, the orphan G protein-coupled receptor, Gpr88, is highly expressed in brain regions implicated in the pathophysiology of and is modulated by treatments for schizophrenia. We compared striatal function of Gpr88 knockout mice (Gpr88KOs) to wild-type mice using molecular, neurochemical and behavioral tests. Gpr88KOs lacked expression of Gpr88 in striatum, nucleus accumbens and layer IV of cortex. Gpr88KOs had normal striatal dopamine D2 receptor density and affinity and DARPP-32 expression but Gpr88KOs had higher basal striatal phosphorylated DARPP-32 Thr-34. In vivo microdialysis detected lower basal dopamine in Gpr88KOs while amphetamine-induced dopamine release was normal. Behaviorally, Gpr88KOs demonstrated disrupted prepulse inhibition of startle (PPI) and increased sensitivity to apomorphine-induced climbing and stereotypy (AICS) and amphetamine-stimulated locomotor activity. Antipsychotic administration to Gpr88KOs normalized the PPI deficit and blocked AICS. The modulatory role of Gpr88 in striatal dopamine function suggests it may be a new target for treatments for psychiatric disorders.
Molecular and Cellular Neuroscience 09/2009; 42(4):438-47. · 3.66 Impact Factor
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Steven M Grauer,
Virginia L Pulito,
Rachel L Navarra,
Michele P Kelly,
Cody Kelley,
Radka Graf,
Barbara Langen,
Sheree Logue,
Julie Brennan,
Lixin Jiang,
Erik Charych,
Ute Egerland,
Feng Liu, Karen L Marquis,
Michael Malamas,
Thorsten Hage,
Thomas A Comery,
Nicholas J Brandon
[show abstract]
[hide abstract]
ABSTRACT: Following several recent reports that suggest that dual cAMP and cGMP phosphodiesterase 10A (PDE10A) inhibitors may present a novel mechanism to treat positive symptoms of schizophrenia, we sought to extend the preclinical characterization of two such compounds, papaverine [1-(3,4-dimethoxybenzyl)-6,7-dimethoxyisoquinoline] and MP-10 [2-{[4-(1-methyl-4-pyridin-4-yl-1H-pyrazol-3-yl)phenoxy]methyl}quinoline], in a variety of in vivo and in vitro assays. Both of these compounds were active in a range of antipsychotic models, antagonizing apomorphine-induced climbing in mice, inhibiting conditioned avoidance responding in both rats and mice, and blocking N-methyl-D-aspartate antagonist-induced deficits in prepulse inhibition of acoustic startle response in rats, while improving baseline sensory gating in mice, all of which strengthen previously reported observations. These compounds also demonstrated activity in several assays intended to probe negative symptoms and cognitive deficits, two disease domains that are underserved by current treatments, with both compounds showing an ability to increase sociality in BALB/cJ mice in the social approach/social avoidance assay, enhance social odor recognition in mice and, in the case of papaverine, improve novel object recognition in rats. Biochemical characterization of these compounds has shown that PDE10A inhibitors modulate both the dopamine D1-direct and D2-indirect striatal pathways and regulate the phosphorylation status of a panel of glutamate receptor subunits in the striatum. It is striking that PDE10A inhibition increased the phosphorylation of the (+/-)-alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid receptor GluR1 subunit at residue serine 845 at the cell surface. Together, our results suggest that PDE10A inhibitors alleviate both dopaminergic and glutamatergic dysfunction thought to underlie schizophrenia, which may contribute to the broad-spectrum efficacy.
Journal of Pharmacology and Experimental Therapeutics 09/2009; 331(2):574-90. · 3.83 Impact Factor
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Robert H Ring,
Lee E Schechter,
Sarah K Leonard,
Jason M Dwyer,
Brian J Platt,
Radka Graf,
Steven Grauer,
Claudine Pulicicchio,
Lynn Resnick,
Zia Rahman,
Stacey J Sukoff Rizzo,
Bin Luo,
Chad E Beyer,
Sheree F Logue, Karen L Marquis,
Zoë A Hughes,
Sharon Rosenzweig-Lipson
[show abstract]
[hide abstract]
ABSTRACT: The widely reported effects of oxytocin (OT) on CNS function has generated considerable interest in the therapeutic potential for targeting this system for a variety of human psychiatric diseases, including anxiety disorders, autism, schizophrenia, and depression. The utility of synthetic OT, as both a research tool and neurotherapeutic, is limited by the physiochemical properties inherent in most neuropeptides, notably its short half-life and poor blood brain barrier penetration. Subsequently, the discovery and development of non-peptide molecules that act as selective agonists of the oxytocin receptor (OTR) has been an important goal of the field. In this study, we report the receptor and behavioral pharmacology of WAY-267464, a first generation small-molecule OTR agonist. WAY-267464 is a high-affinity, potent, and selective (vs. V1a, V2, V1b) agonist of the OTR. In assays measuring both behavioral (four-plate test, elevated zero maze) and autonomic (stress-induced hyperthermia) parameters of the anxiety response, WAY-267464 exhibits an anxiolytic-like profile similar to OT. We have demonstrated that the anxiolytic-like profile of WAY-267464 is mediated through central sites of action. WAY-267464 also significantly reverses disruption in prepulse inhibition of the acoustic startle reflex induced by either MK-801 or amphetamine, similar to the antipsychotic-like effects previously reported for OT. Interestingly, in the mouse tail suspension test, WAY-267464 failed to produce changes in immobility that are seen with OT, raising the question of whether the antidepressant-like activity of OT may be working independently of the OTR. A selective OTR antagonist also failed to block the effects of OT on immobility in the TST. The significance of these findings for shaping the clinical development of OTR agonists is discussed.
Neuropharmacology 08/2009; 58(1):69-77. · 4.81 Impact Factor
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Sanbing Shen,
Bing Lang,
Chizu Nakamoto,
Feng Zhang,
Jin Pu,
Soh-Leh Kuan,
Christina Chatzi,
Shuisheng He,
Iain Mackie,
Nicholas J Brandon, Karen L Marquis,
Mark Day,
Orest Hurko,
Colin D McCaig,
Gernot Riedel,
David St Clair
[show abstract]
[hide abstract]
ABSTRACT: Disrupted-in-Schizophrenia-1 (DISC1), identified by positional cloning of a balanced translocation (1;11) with the breakpoint in intron 8 of a large Scottish pedigree, is associated with a range of neuropsychiatric disorders including schizophrenia. To model this mutation in mice, we have generated Disc1(tr) transgenic mice expressing 2 copies of truncated Disc1 encoding the first 8 exons using a bacterial artificial chromosome (BAC). With this partial simulation of the human situation, we have discovered a range of phenotypes including a series of novel features not previously reported. Disc1(tr) transgenic mice display enlarged lateral ventricles, reduced cerebral cortex, partial agenesis of the corpus callosum, and thinning of layers II/III with reduced neural proliferation at midneurogenesis. Parvalbumin GABAergic neurons are reduced in the hippocampus and medial prefrontal cortex, and displaced in the dorsolateral frontal cortex. In culture, transgenic neurons grow fewer and shorter neurites. Behaviorally, transgenic mice exhibit increased immobility and reduced vocalization in depression-related tests, and impairment in conditioning of latent inhibition. These abnormalities in Disc1(tr) transgenic mice are consistent with findings in severe schizophrenia.
Journal of Neuroscience 11/2008; 28(43):10893-904. · 7.11 Impact Factor
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Feng Liu,
Steve Grauer,
Cody Kelley,
Rachel Navarra,
Radka Graf,
Guoming Zhang,
Peter J Atkinson,
Michael Popiolek,
Caitlin Wantuch,
Xavier Khawaja, [......],
Claudine Pulicicchio,
Mark Day,
Adam Gilbert,
Mark H Pausch,
Nicholas J Brandon,
Chad E Beyer,
Tom A Comery,
Sheree Logue,
Sharon Rosenzweig-Lipson, Karen L Marquis
[show abstract]
[hide abstract]
ABSTRACT: Positive allosteric modulators (PAMs) of metabotropic glutamate receptor subtype 5 (mGlu5) enhance N-methyl-d-aspartate receptor function and may represent a novel approach for the treatment of schizophrenia. ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]oxadiazol-5-yl]-piperidin-1-yl}-methanone], a recently identified potent and selective mGlu5 PAM, increased (9-fold) the response to threshold concentration of glutamate (50 nM) in fluorometric Ca(2+) assays (EC(50) = 170 nM) in human embryonic kidney 293 cells expressing rat mGlu5. In the same system, ADX47273 dose-dependently shifted mGlu5 receptor glutamate response curve to the left (9-fold at 1 microM) and competed for binding of [(3)H]2-methyl-6-(phenylethynyl)pyridine (K(i) = 4.3 microM), but not [(3)H]quisqualate. In vivo, ADX47273 increased extracellular signal-regulated kinase and cAMP-responsive element-binding protein phosphorylation in hippocampus and prefrontal cortex, both of which are critical for glutamate-mediated signal transduction mechanisms. In models sensitive to antipsychotic drug treatment, ADX47273 reduced rat-conditioned avoidance responding [minimal effective dose (MED) = 30 mg/kg i.p.] and decreased mouse apomorphine-induced climbing (MED = 100 mg/kg i.p.), with little effect on stereotypy or catalepsy. Furthermore, ADX47273 blocked phencyclidine, apomorphine, and amphetamine-induced locomotor activities (MED = 100 mg/kg i.p.) in mice and decreased extracellular levels of dopamine in the nucleus accumbens, but not in the striatum, in rats. In cognition models, ADX47273 increased novel object recognition (MED = 1 mg/kg i.p.) and reduced impulsivity in the five-choice serial reaction time test (MED = 10 mg/kg i.p.) in rats. Taken together, these effects are consistent with the hypothesis that allosteric potentiation of mGlu5 may provide a novel approach for development of antipsychotic and procognitive agents.
Journal of Pharmacology and Experimental Therapeutics 09/2008; 327(3):827-39. · 3.83 Impact Factor
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Feng Liu,
Mark Day,
Luis C Muñiz,
Daniel Bitran,
Robert Arias,
Raquel Revilla-Sanchez,
Steve Grauer,
Guoming Zhang,
Cody Kelley,
Virginia Pulito,
Amy Sung,
Ronald F Mervis,
Rachel Navarra,
Warren D Hirst,
Peter H Reinhart, Karen L Marquis,
Stephen J Moss,
Menelas N Pangalos,
Nicholas J Brandon
[show abstract]
[hide abstract]
ABSTRACT: Estrogens have long been implicated in influencing cognitive processes, yet the molecular mechanisms underlying these effects and the roles of the estrogen receptors alpha (ERalpha) and beta (ERbeta) remain unclear. Using pharmacological, biochemical and behavioral techniques, we demonstrate that the effects of estrogen on hippocampal synaptic plasticity and memory are mediated through ERbeta. Selective ERbeta agonists increased key synaptic proteins in vivo, including PSD-95, synaptophysin and the AMPA-receptor subunit GluR1. These effects were absent in ERbeta knockout mice. In hippocampal slices, ERbeta activation enhanced long-term potentiation, an effect that was absent in slices from ERbeta knockout mice. ERbeta activation induced morphological changes in hippocampal neurons in vivo, including increased dendritic branching and increased density of mushroom-type spines. An ERbeta agonist, but not an ERalpha agonist, also improved performance in hippocampus-dependent memory tasks. Our data suggest that activation of ERbeta can regulate hippocampal synaptic plasticity and improve hippocampus-dependent cognition.
Nature Neuroscience 04/2008; 11(3):334-43. · 15.53 Impact Factor
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[show abstract]
[hide abstract]
ABSTRACT: Modulating activity at the 5-HT(2C) receptor holds a tremendous amount of therapeutic promise in multiple psychiatric indications. However, the signaling and regulation of the 5-HT(2C) receptor is highly complex due to multiple signaling pathways and agonist-directed trafficking of this receptor. Moreover, the 5-HT(2C) receptor is differentially regulated via RNA editing in multiple psychiatric disorders and following either pharmacological or environmental manipulation. Direct and indirect data suggest that both agonists and antagonists may provide benefits in several disorders. The current review highlights the underlying complexities of this area and provides the rationale for using 5-HT(2C) agonists in the treatment of both schizophrenia and depressive disorders.
Drug News & Perspectives 12/2007; 20(9):565-71. · 2.21 Impact Factor
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Sharon Rosenzweig-Lipson,
Annmarie Sabb,
Gary Stack,
Paul Mitchell,
Irwin Lucki,
Jessica E Malberg,
Steve Grauer,
Julie Brennan,
John F Cryan,
Stacey J Sukoff Rizzo,
John Dunlop,
James E Barrett, Karen L Marquis
[show abstract]
[hide abstract]
ABSTRACT: Activation of one or more of the serotonin (5-HT) receptors may play a role in mediating the antidepressant effects of SSRIs.
The present studies were conducted to evaluate the effects of the novel 5-HT2C receptor agonist WAY-163909 in animal models of antidepressant activity (forced swim test (FST), resident-intruder, olfactory bulbectomy (BULB)), in a schedule-induced polydipsia (SIP) model of obsessive-compulsive disorder and in a model for evaluating sexual dysfunction.
WAY-163909 (10 mg/kg, i.p. or s.c.) decreased immobility time in Wistar-Kyoto rats in the FST, effects that were reversed by the 5-HT2C/2B receptor antagonist SB 206553. Moreover, in Sprague-Dawley rats, the profile of WAY-163909 (decreased immobility, increased swimming) in the FST was comparable to the effects of SSRIs. Acute treatment with WAY-163909 (0.33 mg/kg, s.c.) decreased rodent aggression at doses lower than those required for decreasing total behavior. Administration of WAY-163909 (3 mg/kg, i.p.) for 5 or 21 days decreased the BULB-induced hyperactivity in rats. Additionally, acute administration of WAY-163909 (3 mg/kg, i.p.) decreased adjunctive drinking in a SIP model. The effects of WAY-163909 were reversed by the 5-HT(2C/2B) receptor antagonist SB 206553 and the selective 5-HT2C receptor antagonist SB 242084. Chronic administration of WAY-163909 produced deficits in sexual function at doses higher (10 mg/kg, i.p.) than those required for antidepressant-like effects in the BULB model.
Taken together, these results demonstrate that the novel 5-HT2C receptor agonist WAY-163909 produces rapid onset antidepressant-like effects in animal models and may be a novel treatment for depression.
Psychopharmacologia 07/2007; 192(2):159-70. · 4.08 Impact Factor
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Karen L Marquis,
Annmarie L Sabb,
Sheree F Logue,
Julie A Brennan,
Michael J Piesla,
Tom A Comery,
Steven M Grauer,
Charles R Ashby,
Huy Q Nguyen,
Lee A Dawson,
James E Barrett,
Gary Stack,
Herbert Y Meltzer,
Boyd L Harrison,
Sharon Rosenzweig-Lipson
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ABSTRACT: Serotonin-2C (5-HT2C) receptor antagonists and agonists have been shown to affect dopamine (DA) neurotransmission, with agonists selectively decreasing mesolimbic DA. As antipsychotic efficacy is proposed to be associated with decreased mesolimbic DA neurotransmission by virtue of DA D2 receptor antagonism, the 5-HT2C-selective receptor agonist, WAY-163909 [(7bR,10aR)-1,2, 3,4,8,9,10,10a-octahydro-7bH-cyclopenta-[b][1,4]diazepino[6,7, 1hi]indole], was evaluated in animal models of schizophrenia and in vivo microdialysis and electrophysiology to determine the effects on mesolimbic and nigrostriatal DA neurotransmission. Similar to clozapine, WAY-163909 (1.7-30 mg/kg i.p.) decreased apomorphine-induced climbing with little effect on stereotypy and no significant induction of catalepsy. WAY-163909 (0.3-3 mg/kg s.c.) more potently reduced phencyclidine-induced locomotor activity compared with d-amphetamine with no effect on spontaneous activity. WAY-163909 (1.7-17 mg/kg i.p.) reversed MK-801 (5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate)- and DOI [1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane]-disrupted prepulse inhibition of startle (PPI) and improved PPI in DBA/2N mice. In conditioned avoidance responding, WAY-163909 (0.3-3 mg/kg i.p.; 1-17 mg/kg p.o.) reduced avoidance responding, an effect blocked by the 5-HT(2B/2C) receptor antagonist SB 206553 [5-methyl-1-(3-pyridylcarbamoyl)-1,2,3,5-tetrahydropyrrolo[2,3-f]indole]. WAY-163909 (10 mg/kg s.c.) selectively decreased extracellular levels of DA in the nucleus accumbens without affecting the striatum. Likewise, in vivo electrophysiological recordings showed a decrease in the number of spontaneously firing DA neurons in the ventral tegmental area but not in the substantia nigra with both acute and chronic (21-day) administration of WAY-163909 (1-10 mg/kg i.p.). Thus, the profile of the 5-HT2C selective receptor agonist WAY-163909 is similar to that of an atypical antipsychotic and additionally may have rapid onset properties.
Journal of Pharmacology and Experimental Therapeutics 02/2007; 320(1):486-96. · 3.83 Impact Factor
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Julia N Heinrich,
Julie Brennan,
Margaret H Lai,
Kelly Sullivan,
Geoff Hornby,
Mike Popiolek,
Li-Xin Jiang,
Mark H Pausch,
Gary Stack, Karen L Marquis,
Terrance H Andree
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ABSTRACT: The pharmacology of aplindore (DAB-452) was characterized in CHO-K1 cells stably transfected with the human dopamine D(2) receptor short isoform (CHO-D(2s)) and in a behavioral model for post-synaptic agonism in rats. In [(3)H]-spiperone competition binding studies, aplindore showed high affinity for dopamine D(2) and D(3) receptors and low affinity for the dopamine D(4), serotonin (5-HT)(1A), 5-HT(2) receptors and the alpha1-adrenoceptor. The high potency partial agonist activity of aplindore was demonstrated in [(35)S]guanosine 5'-O-(3-thiotriphosphate) ([(35)S]GTPgammaS) binding, extracellular signal-regulated kinase (ERK)-phosphorylation and intracellular calcium flux assay using fluorometric plate reader ([Ca(2+)](i)-FLIPR) format. The [Ca(2+)](i)-FLIPR assay was conducted with CHO-D(2S) receptor cells also stably expressing chimeric G(alphaq/o)-proteins. In all assay modalities, the potencies and intrinsic activities of aplindore were lower than dopamine and higher than aripiprazole. In contrast to the [(35)S]GTPgammaS binding and ERK-phosphorylation assays, the [Ca(2+)](i)-FLIPR assay was able to detect the low partial agonist activity of SDZ 208-912. In unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats, aplindore induced contralateral turning, which was blocked by the dopamine D(2) receptor antagonist raclopride. The dopamine D(2) receptor selective partial agonist profile of aplindore suggests that it should be effective for the treatment of dopaminergic-based disorders, such as schizophrenia and Parkinson's disease.
European Journal of Pharmacology 01/2007; 552(1-3):36-45. · 2.52 Impact Factor
