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1.
Bioorg Med Chem Lett ; 22(18): 5876-84, 2012 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-22902656

RESUMO

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).


Assuntos
Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Triazinas/farmacologia , Administração Oral , Animais , Cristalografia por Raios X , Maleato de Dizocilpina/antagonistas & inibidores , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Humanos , Hipercinese/induzido quimicamente , Hipercinese/tratamento farmacológico , Modelos Moleculares , Estrutura Molecular , Inibidores de Fosfodiesterase/administração & dosagem , Inibidores de Fosfodiesterase/química , Ratos , Relação Estrutura-Atividade , Triazinas/administração & dosagem , Triazinas/química
2.
Handb Exp Pharmacol ; (213): 147-65, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23027415

RESUMO

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.


Assuntos
Esquizofrenia/tratamento farmacológico , Agonistas do Receptor 5-HT2 de Serotonina/uso terapêutico , Compostos Heterocíclicos de 4 ou mais Anéis/uso terapêutico , Humanos , Edição de RNA , Pesquisa Translacional Biomédica
3.
Nat Neurosci ; 11(3): 334-43, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-18297067

RESUMO

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.


Assuntos
Receptor beta de Estrogênio/metabolismo , Estrogênios/metabolismo , Hipocampo/metabolismo , Memória/fisiologia , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Animais , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/efeitos dos fármacos , Proteína de Ligação ao Elemento de Resposta ao AMP Cíclico/metabolismo , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/metabolismo , Estradiol/metabolismo , Estradiol/farmacologia , Receptor beta de Estrogênio/agonistas , Receptor beta de Estrogênio/genética , Estrogênios/agonistas , Estrogênios/farmacologia , Feminino , Hipocampo/citologia , Hipocampo/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Potenciação de Longa Duração/fisiologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Memória/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Plasticidade Neuronal/efeitos dos fármacos , Neurônios/citologia , Neurônios/efeitos dos fármacos , Técnicas de Cultura de Órgãos , Ovariectomia , Fosforilação/efeitos dos fármacos , Ratos , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/fisiologia
4.
J Neurochem ; 113(3): 601-14, 2010 May.
Artigo em Inglês | MEDLINE | ID: mdl-20096092

RESUMO

The 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.


Assuntos
Córtex Cerebral/metabolismo , Regulação da Expressão Gênica/fisiologia , Isolamento Social/psicologia , Animais , Comportamento Animal/fisiologia , Córtex Cerebral/química , Córtex Cerebral/ultraestrutura , Biologia Computacional , DNA/biossíntese , DNA/genética , Masculino , Microdiálise , Atividade Motora/fisiologia , Família Multigênica , Análise de Sequência com Séries de Oligonucleotídeos , RNA/biossíntese , RNA/genética , RNA Complementar/biossíntese , RNA Complementar/genética , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Estresse Psicológico/genética , Estresse Psicológico/psicologia , Sinapses/fisiologia , Fatores de Transcrição
5.
J Pharmacol Exp Ther ; 332(1): 190-201, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19828876

RESUMO

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.


Assuntos
Antidepressivos/farmacologia , Antipsicóticos/farmacologia , Benzoxazóis/farmacologia , Agonistas de Dopamina/farmacologia , Indenos/farmacologia , Receptores de Dopamina D2/agonistas , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Animais , Antidepressivos/química , Antipsicóticos/química , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Benzoxazóis/química , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Células CHO , Cricetinae , Cricetulus , Dopamina/metabolismo , Agonistas de Dopamina/química , Avaliação Pré-Clínica de Medicamentos , Humanos , Indenos/química , Masculino , Camundongos , Camundongos Endogâmicos , Microdiálise , Atividade Motora/efeitos dos fármacos , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Serotonina/metabolismo , Antagonistas do Receptor 5-HT1 de Serotonina , Antagonistas do Receptor 5-HT2 de Serotonina , Inibidores Seletivos de Recaptação de Serotonina/química , Transfecção
6.
Bioorg Med Chem Lett ; 20(9): 2983-6, 2010 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-20347298

RESUMO

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.


Assuntos
Antipsicóticos/química , Agonistas de Dopamina/química , Quinolonas/química , Esquizofrenia/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/química , Animais , Antipsicóticos/síntese química , Antipsicóticos/uso terapêutico , Modelos Animais de Doenças , Agonistas de Dopamina/síntese química , Agonistas de Dopamina/uso terapêutico , Quinolonas/síntese química , Quinolonas/uso terapêutico , Receptor 5-HT1A de Serotonina/química , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Dopamina D2/agonistas , Receptores de Dopamina D2/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Relação Estrutura-Atividade
7.
Mol Cell Neurosci ; 42(4): 438-47, 2009 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-19796684

RESUMO

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.


Assuntos
Corpo Estriado/metabolismo , Dopamina/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Animais , Antipsicóticos/farmacologia , Apomorfina , Comportamento Animal/efeitos dos fármacos , Comportamento Animal/fisiologia , Encéfalo/anatomia & histologia , Encéfalo/metabolismo , Corpo Estriado/citologia , Agonistas de Dopamina/farmacologia , Antagonistas de Dopamina/farmacologia , Fosfoproteína 32 Regulada por cAMP e Dopamina/metabolismo , Feminino , Haloperidol/farmacologia , Humanos , Masculino , Camundongos , Camundongos Knockout , Atividade Motora/efeitos dos fármacos , Atividade Motora/fisiologia , Testes Neuropsicológicos , Receptores de Dopamina D2/metabolismo , Receptores Acoplados a Proteínas G/genética , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Risperidona/farmacologia
8.
J Neurosci ; 28(43): 10893-904, 2008 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-18945897

RESUMO

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.


Assuntos
Comportamento Animal/fisiologia , Mutação , Proteínas do Tecido Nervoso/genética , Neurônios/patologia , Fenótipo , Esquizofrenia/genética , Fatores Etários , Análise de Variância , Animais , Animais Recém-Nascidos , Bromodesoxiuridina/metabolismo , Células Cultivadas , Córtex Cerebral/citologia , Modelos Animais de Doenças , Embrião de Mamíferos , Regulação da Expressão Gênica/genética , Proteínas de Fluorescência Verde/biossíntese , Elevação dos Membros Posteriores/métodos , Inibição Psicológica , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neuritos/efeitos dos fármacos , Neuritos/patologia , Neurônios/efeitos dos fármacos , Parvalbuminas/metabolismo , Esquizofrenia/patologia , Esquizofrenia/fisiopatologia , Natação
9.
J Pharmacol Exp Ther ; 331(2): 574-90, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19661377

RESUMO

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.


Assuntos
Antipsicóticos , Cognição/efeitos dos fármacos , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Pirazóis/farmacologia , Quinolinas/farmacologia , Psicologia do Esquizofrênico , Animais , Apomorfina/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Catalepsia/induzido quimicamente , Catalepsia/prevenção & controle , Maleato de Dizocilpina/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neostriado/efeitos dos fármacos , Neostriado/metabolismo , Ratos , Ratos Sprague-Dawley , Reflexo de Sobressalto/efeitos dos fármacos , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Comportamento Social , Comportamento Estereotipado/efeitos dos fármacos
10.
Bioorg Med Chem Lett ; 19(19): 5552-5, 2009 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-19720528

RESUMO

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.


Assuntos
Carbazóis/química , Agonistas de Dopamina/química , Receptores de Dopamina D2/agonistas , Esquizofrenia/tratamento farmacológico , Inibidores Seletivos de Recaptação de Serotonina/química , Antagonistas do Receptor 5-HT1 de Serotonina , Animais , Carbazóis/síntese química , Carbazóis/farmacologia , Modelos Animais de Doenças , Agonistas de Dopamina/síntese química , Agonistas de Dopamina/farmacologia , Ratos , Receptor 5-HT1A de Serotonina/metabolismo , Receptores de Dopamina D2/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/síntese química , Inibidores Seletivos de Recaptação de Serotonina/farmacologia
11.
J Pharmacol Exp Ther ; 327(3): 827-39, 2008 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-18753411

RESUMO

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.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Antipsicóticos/farmacologia , Cognição/efeitos dos fármacos , Oxidiazóis/farmacologia , Piperidinas/farmacologia , Receptores de Glutamato Metabotrópico/efeitos dos fármacos , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Linhagem Celular , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos , Hipocampo/metabolismo , Humanos , Córtex Pré-Frontal/metabolismo , Ratos , Receptor de Glutamato Metabotrópico 5
12.
Psychopharmacology (Berl) ; 192(2): 159-70, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17297636

RESUMO

RATIONALE: Activation of one or more of the serotonin (5-HT) receptors may play a role in mediating the antidepressant effects of SSRIs. OBJECTIVE: 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. RESULTS: 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. CONCLUSIONS: 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.


Assuntos
Antidepressivos/farmacologia , Azepinas/farmacologia , Depressão/tratamento farmacológico , Indóis/farmacologia , Receptor 5-HT2C de Serotonina/efeitos dos fármacos , Agonistas do Receptor de Serotonina/farmacologia , Agressão/efeitos dos fármacos , Animais , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Azepinas/administração & dosagem , Azepinas/efeitos adversos , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Comportamento de Ingestão de Líquido/efeitos dos fármacos , Feminino , Indóis/administração & dosagem , Indóis/efeitos adversos , Masculino , Transtorno Obsessivo-Compulsivo/induzido quimicamente , Transtorno Obsessivo-Compulsivo/tratamento farmacológico , Ratos , Ratos Endogâmicos WKY , Ratos Long-Evans , Ratos Sprague-Dawley , Ratos Wistar , Receptor 5-HT2C de Serotonina/metabolismo , Agonistas do Receptor de Serotonina/administração & dosagem , Agonistas do Receptor de Serotonina/efeitos adversos , Comportamento Sexual Animal/efeitos dos fármacos , Disfunções Sexuais Fisiológicas/induzido quimicamente , Natação
13.
Drug News Perspect ; 20(9): 565-71, 2007 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-18176661

RESUMO

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.


Assuntos
Transtorno Depressivo/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Agonistas do Receptor 5-HT2 de Serotonina , Agonistas do Receptor de Serotonina/uso terapêutico , Animais , Transtorno Depressivo/fisiopatologia , Desenho de Fármacos , Humanos , Receptor 5-HT2C de Serotonina/fisiologia , Esquizofrenia/fisiopatologia , Antagonistas do Receptor 5-HT2 de Serotonina , Antagonistas da Serotonina/farmacologia , Antagonistas da Serotonina/uso terapêutico , Agonistas do Receptor de Serotonina/farmacologia , Transdução de Sinais/efeitos dos fármacos
14.
J Neurosci ; 25(39): 8898-902, 2005 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-16192379

RESUMO

Transgenic mice (Tg2576) overexpressing the Swedish mutation of the human amyloid precursor protein display biochemical, pathological, and behavioral markers consistent with many aspects of Alzheimer's disease, including impaired hippocampal function. Impaired, hippocampal-dependent, contextual fear conditioning (CFC) is observed in mice as young as 20 weeks of age. This impairment can be attenuated after treatment before training with the phosphodiesterase-4 inhibitor rolipram (0.1 mg/kg, i.p.). A rolipram-associated improvement is also observed in the littermate controls, suggesting that the effect of rolipram is independent of beta-amyloid. Acute treatment before training (but not after training or before testing) with the gamma-secretase inhibitor (GSI) N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine-t-butylester (DAPT), at a dose that reduces brain concentrations of beta-amyloid (100 mg/kg), attenuates the impairment in 20- to 65-week-old Tg2576 mice. Importantly, DAPT had no effect on performance of control littermates. These data are supportive of a role of beta-amyloid in the impairment of CFC in Tg2576 mice. Furthermore, they suggest that acute treatment with GSI may provide improved cognitive functioning as well as disease-modifying effects in Alzheimer's disease.


Assuntos
Doença de Alzheimer/metabolismo , Doença de Alzheimer/psicologia , Condicionamento Psicológico/efeitos dos fármacos , Endopeptidases/metabolismo , Inibidores Enzimáticos/farmacologia , Medo , 3',5'-AMP Cíclico Fosfodiesterases/antagonistas & inibidores , Envelhecimento/psicologia , Doença de Alzheimer/genética , Secretases da Proteína Precursora do Amiloide , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Ácido Aspártico Endopeptidases , Cognição/efeitos dos fármacos , Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/psicologia , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4 , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Mutação , Inibidores de Fosfodiesterase/farmacologia , Rolipram/farmacologia , Triglicerídeos/farmacologia , Ácido gama-Aminobutírico/análogos & derivados , Ácido gama-Aminobutírico/farmacologia
15.
Eur J Pharmacol ; 552(1-3): 36-45, 2006 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-17056032

RESUMO

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.


Assuntos
Agonistas de Dopamina/farmacologia , Indóis/farmacologia , Receptores de Dopamina D2/agonistas , Animais , Ligação Competitiva , Células CHO , Cálcio/metabolismo , Cricetinae , Cricetulus , Agonistas de Dopamina/metabolismo , Relação Dose-Resposta a Droga , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Subunidades alfa de Proteínas de Ligação ao GTP/genética , Subunidades alfa de Proteínas de Ligação ao GTP/metabolismo , Guanosina 5'-O-(3-Tiotrifosfato)/metabolismo , Indóis/metabolismo , Masculino , Atividade Motora/efeitos dos fármacos , Oxidopamina/toxicidade , Fosforilação/efeitos dos fármacos , Quimpirol/farmacologia , Ensaio Radioligante , Ratos , Ratos Sprague-Dawley , Receptor 5-HT1A de Serotonina/metabolismo , Receptores Adrenérgicos alfa 1/metabolismo , Receptores de Dopamina D2/genética , Receptores de Dopamina D2/metabolismo , Receptores de Dopamina D4/metabolismo , Receptores 5-HT2 de Serotonina/metabolismo , Substância Negra/efeitos dos fármacos , Substância Negra/patologia , Substância Negra/fisiopatologia
16.
Psychopharmacology (Berl) ; 218(4): 635-47, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21643676

RESUMO

RATIONALE: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.


Assuntos
Transtornos Cognitivos/tratamento farmacológico , Piridinas/farmacologia , Risperidona/farmacologia , Esquizofrenia/tratamento farmacológico , Ureia/análogos & derivados , Animais , Antipsicóticos/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Transtornos Cognitivos/etiologia , Avaliação Pré-Clínica de Medicamentos , Interações Medicamentosas , Quimioterapia Combinada , Masculino , Memória/efeitos dos fármacos , Camundongos , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley , Receptores Nicotínicos/efeitos dos fármacos , Receptores Nicotínicos/metabolismo , Esquizofrenia/fisiopatologia , Ureia/farmacologia , Receptor Nicotínico de Acetilcolina alfa7
17.
J Med Chem ; 54(21): 7621-38, 2011 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-21988093

RESUMO

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.


Assuntos
Antipsicóticos/síntese química , Inibidores de Fosfodiesterase/síntese química , Diester Fosfórico Hidrolases/metabolismo , Pirazinas/síntese química , Administração Oral , Animais , Antipsicóticos/farmacocinética , Antipsicóticos/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Sítios de Ligação , Cristalografia por Raios X , AMP Cíclico/química , AMP Cíclico/metabolismo , GMP Cíclico/metabolismo , Cães , Feminino , Humanos , Hidrólise , Hipercinese/tratamento farmacológico , Técnicas In Vitro , Isoenzimas/química , Isoenzimas/metabolismo , Ligantes , Masculino , Camundongos , Microssomos/metabolismo , Modelos Moleculares , Inibidores de Fosfodiesterase/farmacocinética , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/química , Conformação Proteica , Pirazinas/farmacocinética , Pirazinas/farmacologia , Ratos , Ratos Sprague-Dawley , Ratos Wistar , Proteínas Recombinantes/química , Estereoisomerismo , Comportamento Estereotipado/efeitos dos fármacos , Relação Estrutura-Atividade
18.
J Med Chem ; 53(11): 4399-411, 2010 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-20450197

RESUMO

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.


Assuntos
Descoberta de Drogas/métodos , Inibidores de Fosfodiesterase/química , Inibidores de Fosfodiesterase/farmacologia , Diester Fosfórico Hidrolases/metabolismo , Pirazinas/química , Pirazinas/farmacologia , Animais , Feminino , Humanos , Modelos Moleculares , Diester Fosfórico Hidrolases/química , Conformação Proteica , Relação Quantitativa Estrutura-Atividade , Ratos , Ratos Wistar
19.
Neuropharmacology ; 58(1): 69-77, 2010 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19615387

RESUMO

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.


Assuntos
Ansiolíticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Ocitocina/farmacologia , Receptores de Ocitocina/agonistas , Estimulação Acústica/efeitos adversos , Animais , Aprendizagem da Esquiva/efeitos dos fármacos , Benzodiazepinas/farmacologia , Benzodiazepinas/uso terapêutico , Células CHO , Cricetinae , Cricetulus , Febre/tratamento farmacológico , Febre/etiologia , Elevação dos Membros Posteriores/métodos , Humanos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Inibição Neural/efeitos dos fármacos , Ocitocina/agonistas , Ligação Proteica/efeitos dos fármacos , Pirazóis/farmacologia , Pirazóis/uso terapêutico , Ratos , Ratos Sprague-Dawley , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Estresse Psicológico/complicações
20.
J Med Chem ; 53(11): 4379-89, 2010 Jun 10.
Artigo em Inglês | MEDLINE | ID: mdl-20465311

RESUMO

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.


Assuntos
Agonistas Nicotínicos/síntese química , Agonistas Nicotínicos/farmacologia , Piridinas/síntese química , Piridinas/farmacologia , Receptores Nicotínicos/metabolismo , Ureia/análogos & derivados , Ureia/síntese química , Ureia/farmacologia , Administração Oral , Animais , Humanos , Concentração Inibidora 50 , Masculino , Modelos Moleculares , Agonistas Nicotínicos/administração & dosagem , Agonistas Nicotínicos/farmacocinética , Conformação Proteica , Piridinas/administração & dosagem , Piridinas/farmacocinética , Ratos , Receptores Nicotínicos/química , Relação Estrutura-Atividade , Especificidade por Substrato , Ureia/administração & dosagem , Ureia/farmacocinética , Receptor Nicotínico de Acetilcolina alfa7
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