RESUMO
SAM-760 [(2-methyl-1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-benzo[d]imidazole)], a 5HT6 antagonist, was investigated in humans for the treatment of Alzheimer's disease. In liver microsomes and recombinant cytochrome P450 (P450) isozymes, SAM-760 was predominantly metabolized by CYP3A (â¼85%). Based on these observations and an expectation of a 5-fold magnitude of interaction with moderate to strong CYP3A inhibitors, a clinical DDI study was performed. In the presence of ketoconazole, the mean Cmax and area under the plasma concentration-time curve from time zero extrapolated to infinite time values of SAM-760 showed only a modest increase by 30% and 38%, respectively. In vitro investigation of this unexpectedly low interaction was undertaken using [14C]SAM-760. Radiometric profiling in human hepatocytes confirmed all oxidative metabolites previously observed with unlabeled SAM-760; however, the predominant radiometric peak was an unexpected polar metabolite that was insensitive to the pan-P450 inhibitor 1-aminobenzotriazole. In human hepatocytes, radiometric integration attributed 43% of the total metabolism of SAM-760 to this non-P450 pathway. Using an authentic standard, this predominant metabolite was confirmed as benzenesulfinic acid. Additional investigation revealed that the benzenesulfinic acid metabolite may be a novel, nonenzymatic, thiol-mediated reductive cleavage of an aryl sulfonamide group of SAM-760. We also determined the relative contribution of P450 to the metabolism of SAM-760 in human hepatocytes by following the rate of formation of oxidative metabolites in the presence and absence of P450 isoform-specific inhibitors. The P450-mediated oxidative metabolism of SAM-760 was still primarily attributed to CYP3A (33%), with minor contributions from P450 isoforms CYP2C19 and CYP2D6. Thus, the disposition of [14C]SAM-760 in human hepatocytes via novel sulfonamide metabolism and CYP3A verified the lower than expected clinical DDI when SAM-760 was coadministered with ketoconazole.
Assuntos
Interações Medicamentosas/fisiologia , Imidazóis/metabolismo , Cetoconazol/metabolismo , Piperazinas/metabolismo , Receptores de Serotonina/metabolismo , Inibidores Seletivos de Recaptação de Serotonina/metabolismo , Sulfonamidas/metabolismo , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Inibidores do Citocromo P-450 CYP3A/metabolismo , Hepatócitos/metabolismo , Humanos , Isoenzimas/metabolismo , Microssomos Hepáticos/metabolismo , PiperazinaRESUMO
Several anti-amyloid ß (Aß) antibodies are under evaluation for the treatment of Alzheimer's disease (AD). Clinical studies using the N-terminal-directed anti-Aß antibody bapineuzumab have demonstrated reduced brain PET-Pittsburg-B signals, suggesting the reduction of Aß plaques, and reduced levels of total and phosphorylated tau protein in the CSF of treated AD patients. Preclinical studies using 3D6 (the murine form of bapineuzumab) have demonstrated resolution of Aß plaque and vascular burdens, neuritic dystrophy, and preservation of synaptic density in the transgenic APP mouse models. In contrast, few studies have evaluated the direct interaction of this antibody with synaptotoxic soluble Aß species. In the current report, we demonstrated that 3D6 binds to soluble, synaptotoxic assemblies of Aß(1-42) and prevents multiple downstream functional consequences in rat hippocampal neurons including changes in glutamate AMPA receptor trafficking, AD-type tau phosphorylation, and loss of dendritic spines. In vivo, we further demonstrated that 3D6 prevents synaptic loss and acutely reverses the behavioral deficit in the contextual fear conditioning task in transgenic mouse models of AD, two endpoints thought to be linked to synaptotoxic soluble Aß moieties. Importantly C-terminal anti-Aß antibodies were ineffective on these endpoints. These results, taken with prior studies, suggest that N-terminal anti-Aß antibodies effectively interact with both soluble and insoluble forms of Aß and therefore appear particularly well suited for testing the Aß hypothesis of AD.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/imunologia , Anticorpos/farmacologia , Anticorpos/uso terapêutico , Epitopos/imunologia , Doença de Alzheimer/complicações , Doença de Alzheimer/genética , Doença de Alzheimer/imunologia , Peptídeos beta-Amiloides/química , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Análise de Variância , Animais , Anticorpos Neutralizantes , Sintomas Comportamentais/tratamento farmacológico , Sintomas Comportamentais/etiologia , Sintomas Comportamentais/imunologia , Biotina/metabolismo , Células Cultivadas , Condicionamento Psicológico/efeitos dos fármacos , Condicionamento Psicológico/fisiologia , Espinhas Dendríticas/efeitos dos fármacos , Modelos Animais de Doenças , Embrião de Mamíferos , Epitopos/metabolismo , Medo/efeitos dos fármacos , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Hipocampo/citologia , Humanos , Camundongos , Camundongos Transgênicos , Proteínas dos Microfilamentos/imunologia , Proteínas dos Microfilamentos/metabolismo , Proteínas Associadas aos Microtúbulos/imunologia , Proteínas Associadas aos Microtúbulos/metabolismo , Mutação/genética , Proteínas do Tecido Nervoso/imunologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/citologia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Neuropeptídeos/imunologia , Neuropeptídeos/metabolismo , Fragmentos de Peptídeos/imunologia , Fosforilação , Ligação Proteica/imunologia , Estrutura Secundária de Proteína , Transporte Proteico/efeitos dos fármacos , Ratos , Receptores de AMPA/metabolismo , Solubilidade , Proteína Vesicular 1 de Transporte de Glutamato/imunologia , Proteína Vesicular 1 de Transporte de Glutamato/metabolismoRESUMO
Phosphodiesterase 11A (PDE11A) is the most recently identified family of phosphodiesterases (PDEs), the only known enzymes to break down cyclic nucleotides. The tissue expression profile of this dual specificity PDE is controversial, and little is understood of its biological function, particularly in the brain. We seek here to determine if PDE11A is expressed in the brain and to understand its function, using PDE11A(-/-) knockout (KO) mice. We show that PDE11A mRNA and protein are largely restricted to hippocampus CA1, subiculum, and the amygdalohippocampal area, with a two- to threefold enrichment in the ventral vs. dorsal hippocampus, equal distribution between cytosolic and membrane fractions, and increasing levels of protein expression from postnatal day 7 through adulthood. Interestingly, PDE11A KO mice show subtle psychiatric-disease-related deficits, including hyperactivity in an open field, increased sensitivity to the glutamate N-methyl-D-aspartate receptor antagonist MK-801, as well as deficits in social behaviors (social odor recognition memory and social avoidance). In addition, PDE11A KO mice show enlarged lateral ventricles and increased activity in CA1 (as per increased Arc mRNA), phenotypes associated with psychiatric disease. The increased sensitivity to MK-801 exhibited by PDE11A KO mice may be explained by the biochemical dysregulation observed around the glutamate alpha-amino-3-hydroxy-5-methyl-4-isozazolepropionic (AMPA) receptor, including decreased levels of phosphorylated-GluR1 at Ser845 and the prototypical transmembrane AMPA-receptor-associated proteins stargazin (gamma2) and gamma8. Together, our data provide convincing evidence that PDE11A expression is restricted in the brain but plays a significant role in regulating brain function.
Assuntos
3',5'-GMP Cíclico Fosfodiesterases/metabolismo , Hipocampo/enzimologia , Transtornos Mentais/enzimologia , 3',5'-GMP Cíclico Fosfodiesterases/deficiência , 3',5'-GMP Cíclico Fosfodiesterases/genética , Animais , Comportamento Animal , Feminino , Regulação Enzimológica da Expressão Gênica , Glutamina/metabolismo , Hipocampo/patologia , Masculino , Transtornos Mentais/genética , Transtornos Mentais/patologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , RNA Mensageiro/genética , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais , Comportamento SocialRESUMO
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 BiomédicaRESUMO
Immunotherapy targeting of amyloid beta (Abeta) peptide in transgenic mouse models of Alzheimer disease (AD) has been widely demonstrated to resolve amyloid deposition as well as associated neuronal, glial, and inflammatory pathologies. These successes have provided the basis for ongoing clinical trials of immunotherapy for treatment of AD in humans. Acute as well as chronic Abeta-targeted immunotherapy has also been demonstrated to reverse Abeta-related behavioral deficits assessing memory in AD transgenic mouse models. We observe that three antibodies targeting the same linear epitope of Abeta, Abeta(3-7), differ in their ability to reverse contextual fear deficits in Tg2576 mice in an acute testing paradigm. Reversal of contextual fear deficit by the antibodies does not correlate with in vitro recognition of Abeta in a consistent or correlative manner. To better define differences in antigen recognition at the atomic level, we determined crystal structures of Fab fragments in complex with Abeta. The conformation of the Abeta peptide recognized by all three antibodies was highly related and is also remarkably similar to that observed in independently reported Abeta:antibody crystal structures. Sequence and structural differences between the antibodies, particularly in CDR3 of the heavy chain variable region, are proposed to account for differing in vivo properties of the antibodies under study. These findings provide a structural basis for immunotherapeutic strategies targeting Abeta species postulated to underlie cognitive deficits in AD.
Assuntos
Doença de Alzheimer/imunologia , Doença de Alzheimer/metabolismo , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/química , Animais , Comportamento Animal , Reagentes de Ligações Cruzadas/farmacologia , Cristalografia por Raios X/métodos , Modelos Animais de Doenças , Epitopos/química , Heterozigoto , Humanos , Cinética , Masculino , Camundongos , Conformação Molecular , Proteínas Recombinantes/químicaRESUMO
On the basis of the previously reported benzimidazole 1,3'-bipyrrolidine benzamides (1), a series of related pyrrolidin-3-yl-N-methylbenzamides were synthesized and evaluated as H(3) receptor antagonists. In particular, compound 32 exhibits potent H(3) receptor binding affinity, improved pharmaceutical properties and a favorable in vivo profile.
Assuntos
Benzamidas/síntese química , Benzamidas/farmacologia , Desenho de Fármacos , Antagonistas dos Receptores Histamínicos H3/síntese química , Antagonistas dos Receptores Histamínicos H3/farmacologia , Pirrolidinas/síntese química , Pirrolidinas/farmacologia , Animais , Benzamidas/química , Benzamidas/farmacocinética , Encéfalo/metabolismo , Transtornos Cognitivos/tratamento farmacológico , Transtornos Cognitivos/fisiopatologia , Diabetes Insípido/tratamento farmacológico , Diabetes Insípido/metabolismo , Modelos Animais de Doenças , Antagonistas dos Receptores Histamínicos H3/química , Antagonistas dos Receptores Histamínicos H3/farmacocinética , Antígenos de Histocompatibilidade/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Microssomos Hepáticos/metabolismo , Terapia de Alvo Molecular , Ligação Proteica , Pirrolidinas/química , Pirrolidinas/farmacocinética , Ratos , Estereoisomerismo , Relação Estrutura-Atividade , Proteínas com Motivo TripartidoRESUMO
As part of our efforts to develop agents for cognitive enhancement, we have been focused on the 5-HT(6) receptor in order to identify potent and selective ligands for this purpose. Herein we report the identification of a novel series of 3-sulfonylindazole derivatives with acyclic amino side chains as potent and selective 5-HT(6) antagonists. The synthesis and detailed SAR of this class of compounds are reported.
Assuntos
Indazóis/farmacologia , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/farmacologia , Células HeLa , Humanos , Indazóis/química , Espectroscopia de Ressonância Magnética , Nootrópicos/química , Nootrópicos/farmacologia , Antagonistas da Serotonina/química , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-AtividadeRESUMO
The amyloid hypothesis states that a variety of neurotoxic beta-amyloid (Abeta) species contribute to the pathogenesis of Alzheimer's disease. Accordingly, a key determinant of disease onset and progression is the appropriate balance between Abeta production and clearance. Enzymes responsible for the degradation of Abeta are not well understood, and, thus far, it has not been possible to enhance Abeta catabolism by pharmacological manipulation. We provide evidence that Abeta catabolism is increased after inhibition of plasminogen activator inhibitor-1 (PAI-1) and may constitute a viable therapeutic approach for lowering brain Abeta levels. PAI-1 inhibits the activity of tissue plasminogen activator (tPA), an enzyme that cleaves plasminogen to generate plasmin, a protease that degrades Abeta oligomers and monomers. Because tPA, plasminogen and PAI-1 are expressed in the brain, we tested the hypothesis that inhibitors of PAI-1 will enhance the proteolytic clearance of brain Abeta. Our data demonstrate that PAI-1 inhibitors augment the activity of tPA and plasmin in hippocampus, significantly lower plasma and brain Abeta levels, restore long-term potentiation deficits in hippocampal slices from transgenic Abeta-producing mice, and reverse cognitive deficits in these mice.
Assuntos
Peptídeos beta-Amiloides/metabolismo , Encéfalo/metabolismo , Fibrinolisina/metabolismo , Fibrinolíticos/metabolismo , Animais , Humanos , Imuno-Histoquímica , Camundongos , Camundongos Transgênicos , Inativadores de Plasminogênio/metabolismo , Ativador de Plasminogênio Tecidual/antagonistas & inibidores , Ativador de Plasminogênio Tecidual/metabolismoRESUMO
Using a focused screen of biogenic amine compounds we identified a novel series of H(3)R antagonists. A preliminary SAR study led to reduction of MW while increasing binding affinity and potency. Optimization of the physical properties of the series led to (S)-6n, with improved brain to plasma exposure and efficacy in both water intake and novel object recognition models.
Assuntos
Benzamidas/química , Benzimidazóis/química , Antagonistas dos Receptores Histamínicos H3/química , Pirrolidinas/química , Receptores Histamínicos H3 , Animais , Benzamidas/sangue , Benzamidas/metabolismo , Benzimidazóis/sangue , Benzimidazóis/metabolismo , Células CACO-2 , Linhagem Celular , Antagonistas dos Receptores Histamínicos H3/sangue , Antagonistas dos Receptores Histamínicos H3/metabolismo , Humanos , Indóis/sangue , Indóis/química , Indóis/metabolismo , Ligação Proteica , Pirrolidinas/sangue , Pirrolidinas/metabolismo , Ratos , Receptores Histamínicos H3/sangue , Receptores Histamínicos H3/metabolismoRESUMO
BACKGROUND: Parkinson's disease (PD) is a progressive neurodegenerative condition characterized by an increasing loss of dopaminergic neurons resulting in motor dysfunction. However, cognitive impairments in PD patients are a common clinical feature that has gained increased attention. OBJECTIVE: The purpose of the current study was to evaluate the effects of an MPTP-induced dopaminergic lesion in mice on social odor recognition (SOR) memory. METHODS: Mice were acutely treated with MPTP and evaluated for memory impairments in the SOR assay and characterized using biochemical and immunohistochemical methods approximately 2 weeks later. RESULTS: Here we demonstrate that SOR memory is sensitive to MPTP treatment and that it correlates with multiple measures of nigrostriatal integrity. MPTP treatment of C57BL/6N mice produced a profound decrease in dopamine levels, dopamine transporter binding and tyrosine hydroxylase immunoreactivity in the striatum. These impairments in stratial dopaminergic function were blocked by pretreatment with the MAO-B inhibitor deprenyl. Changes in the dopaminergic system parallel those observed in SOR with MPTP treatment impairing recognition memory in the absence of a deficit in odor discrimination during learning. Deprenyl pretreatment blocked the MPTP-induced impairment of SOR memory. CONCLUSION: The use of the SOR memory model may provide a preclinical method for evaluating cognitive therapies for PD.
Assuntos
Intoxicação por MPTP/complicações , Intoxicação por MPTP/psicologia , Transtornos da Memória/etiologia , Reconhecimento Psicológico/fisiologia , Predomínio Social , 1-Metil-4-Fenil-1,2,3,6-Tetra-Hidropiridina/farmacologia , Análise de Variância , Animais , Modelos Animais de Doenças , Dopamina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Comportamento Exploratório/efeitos dos fármacos , Intoxicação por MPTP/induzido quimicamente , Intoxicação por MPTP/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Substância Negra/efeitos dos fármacos , Tirosina 3-Mono-Oxigenase/metabolismoRESUMO
The alpha7 nicotinic acetylcholine receptor (nAChR) is a promising target for treatment of cognitive dysfunction associated with Alzheimer's disease and schizophrenia. Here, we report the pharmacological properties of 5-morpholin-4-yl-pentanoic acid (4-pyridin-3-yl-phenyl)-amide [SEN12333 (WAY-317538)], a novel selective agonist of alpha7 nAChR. SEN12333 shows high affinity for the rat alpha7 receptor expressed in GH4C1 cells (K(i) = 260 nM) and acts as full agonist in functional Ca(2+) flux studies (EC(50) = 1.6 microM). In whole-cell patch-clamp recordings, SEN12333 activated peak currents and maximal total charges similar to acetylcholine (EC(50) = 12 microM). The compound did not show agonist activity at other nicotinic receptors tested and acted as a weak antagonist at alpha3-containing receptors. SEN12333 treatment (3 mg/kg i.p.) improved episodic memory in a novel object recognition task in rats in conditions of spontaneous forgetting as well as cognitive disruptions induced via glutamatergic [5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate); MK-801] or cholinergic (scopolamine) mechanisms. This improvement was blocked by the alpha7-selective antagonist methyllycaconitine, indicating that it is mediated by alpha7 activation. SEN12333 also prevented a scopolamine-induced deficit in a passive avoidance task. In models targeting other cognitive domains, including attention and perceptual processing, SEN12333 normalized the apomorphine-induced deficit of prepulse inhibition. Neuroprotection of SEN12333 was demonstrated in quisqualate-lesioned animals in which treatment with SEN12333 (3 mg/kg/day i.p.) resulted in a significant protection of choline acetyltransferase-positive neurons in the lesioned hemisphere. Cumulatively, our results demonstrate that the novel alpha7 nAChR agonist SEN12333 has procognitive and neuroprotective properties, further demonstrating utility of alpha7 agonists for treatment of neurodegenerative and cognitive disorders.
Assuntos
Transtornos Cognitivos/tratamento farmacológico , Morfolinas/uso terapêutico , Doenças Neurodegenerativas/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Agonistas Nicotínicos/uso terapêutico , Piridinas/uso terapêutico , Receptores Nicotínicos/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Cálcio/metabolismo , Linhagem Celular , Cognição/efeitos dos fármacos , Transtornos Cognitivos/metabolismo , Humanos , Masculino , Potenciais da Membrana/efeitos dos fármacos , Estrutura Molecular , Morfolinas/química , Morfolinas/farmacocinética , Morfolinas/farmacologia , Atividade Motora/efeitos dos fármacos , Doenças Neurodegenerativas/metabolismo , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacocinética , Fármacos Neuroprotetores/farmacologia , Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacocinética , Agonistas Nicotínicos/farmacologia , Técnicas de Patch-Clamp , Ligação Proteica , Piridinas/química , Piridinas/farmacocinética , Piridinas/farmacologia , Ensaio Radioligante , Ratos , Ratos Long-Evans , Ratos Wistar , Receptor Nicotínico de Acetilcolina alfa7RESUMO
The alpha7 nicotinic acetylcholine receptor (nAChR) has been implicated in Alzheimer's disease and schizophrenia, leading to efforts targeted toward discovering agonists and positive allosteric modulators (PAMs) of this receptor. In a Ca2+ flux fluorometric imaging plate reader assay, SB-206553 (3,5-dihydro-5-methyl -N-3-pyridinylbenzo [1, 2-b:4,5 -b']-di pyrrole-1(2H)-carboxamide), a compound known as a 5-hydroxytryptamine(2B/2C) receptor antagonist, produced an 8-fold potentiation of the evoked calcium signal in the presence of an EC(20) concentration of nicotine and a corresponding EC(50) of 1.5 muM for potentiation of EC(20) nicotine responses in GH4C1 cells expressing the alpha7 receptor. SB-206553 was devoid of direct alpha7 receptor agonist activity and selective against other nicotinic receptors. Confirmation of the PAM activity of SB-206553 on the alpha7 nAChR was obtained in patch-clamp electrophysiological experiments in GH4C1 cells, where it failed to evoke any detectable currents when applied alone, yet dramatically potentiated the currents evoked by an EC(20) (17 microM) and EC(100) (124 microM) of acetylcholine (ACh). Native nicotinic receptors in CA1 stratum radiatum interneurons of rat hippocampal slices could also be activated by ACh (200 microM), an effect that was entirely blocked by the alpha7-selective antagonist methyllycaconitine (MLA). These ACh currents were potentiated by SB-206553, which increased the area of the current response significantly, resulting in a 40-fold enhancement at 100 microM. In behavioral experiments in rats, SB-206553 reversed an MK-801 (dizocilpine maleate)-induced deficit in the prepulse inhibition of acoustic startle response, an effect attenuated in the presence of MLA. This latter observation provides further evidence in support of the potential therapeutic utility of alpha7 nAChR PAMs in schizophrenia.
Assuntos
Indóis/farmacologia , Piridinas/farmacologia , Receptores Nicotínicos/fisiologia , Receptores 5-HT2 de Serotonina/fisiologia , Antagonistas da Serotonina/farmacologia , Animais , Linhagem Celular , Eletrofisiologia , Hipocampo/efeitos dos fármacos , Hipocampo/fisiologia , Humanos , Rim/embriologia , Técnicas de Patch-Clamp , Ratos , Ratos Wistar , Receptores Nicotínicos/efeitos dos fármacos , Receptores 5-HT2 de Serotonina/efeitos dos fármacos , Receptores 5-HT2 de Serotonina/genética , Transfecção , Receptor Nicotínico de Acetilcolina alfa7RESUMO
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 fármacosRESUMO
As part of our continuing efforts to identify therapeutics for CNS diseases such as schizophrenia and Alzheimer's disease (AD), we have been focused on the 5-HT(6) receptor in order to identify potent and selective ligands as a potential treatment for cognitive dysfunction. Herein we report the identification of a novel series of benzoxazole derivatives as potent 5-HT(6) ligands. The synthesis and detailed SAR of this class of compounds are reported. The compounds have been shown to be full antagonists in a cyclic AMP functional assay.
Assuntos
Benzoxazóis/síntese química , Benzoxazóis/farmacologia , Transtornos Cognitivos/tratamento farmacológico , Modelos Moleculares , Receptores de Serotonina/efeitos dos fármacos , Serotoninérgicos/síntese química , Benzoxazóis/química , Técnicas de Química Combinatória , AMP Cíclico/antagonistas & inibidores , Desenho de Fármacos , Ligantes , Estrutura Molecular , Serotoninérgicos/química , Serotoninérgicos/farmacologia , Relação Estrutura-AtividadeRESUMO
As part of our continuing efforts to identify therapeutics for CNS diseases, such as schizophrenia and Alzheimer's disease (AD), we have been focused on the 5-HT(6) receptor in an attempt to identify ligands as a potential treatment for cognitive dysfunction. Herein we report the identification of a novel series of 1-sulfonylindazole derivatives as potent and selective 5-HT(6) antagonists. The synthesis and SAR of this class of compounds are reported. Several potent compounds in both binding and cyclase functional assays also display good selectivity, microsomal stability, solubility, and brain penetration as well as low cytochrome P450 inhibition. One compound exemplified in this series showed 24% oral bioavailability and in vivo efficacy in a NOR cognition model at 10mg/kg following an oral administration in rats.
Assuntos
Indazóis/química , Indazóis/síntese química , Receptores de Serotonina/química , Administração Oral , Animais , Disponibilidade Biológica , Doenças do Sistema Nervoso Central/tratamento farmacológico , Transtornos Cognitivos/tratamento farmacológico , Desenho de Fármacos , Humanos , Indazóis/farmacologia , Concentração Inibidora 50 , Cinética , Ligantes , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Cognitive dysfunction is a characteristic of various forms of dementia such as Alzheimer's disease (AD) and a core feature of schizophrenia. As part of our continuing efforts to develop agents for cognitive enhancement, we have been focused on the 5-HT(6) receptor-one of the emerging therapeutic targets in this area. Herein, we report the identification of a novel series of 3-piperidinyl-5-sulfonylindazole derivatives as potent 5-HT(6) antagonists. The synthesis and SAR of this class of compounds are reported.
Assuntos
Indazóis/síntese química , Receptores de Serotonina/efeitos dos fármacos , Antagonistas da Serotonina/síntese química , Transtornos Cognitivos/tratamento farmacológico , Demência/tratamento farmacológico , Humanos , Indazóis/farmacologia , Ligantes , Piperidinas/síntese química , Piperidinas/farmacologia , Antagonistas da Serotonina/farmacologia , Ácidos Sulfínicos/síntese química , Ácidos Sulfínicos/farmacologiaRESUMO
Accumulation of beta-amyloid (Abeta), produced by the proteolytic cleavage of amyloid precursor protein (APP) by beta- and gamma-secretase, is widely believed to be associated with Alzheimer's disease (AD). Research around the high-throughput screening hit (S)-4-chlorophenylsulfonyl isoleucinol led to the identification of the Notch-1-sparing (9.5-fold) gamma-secretase inhibitor (S)-N-(5-chlorothiophene-2-sulfonyl)-beta,beta-diethylalaninol 7.b.2 (Abeta(40/42) EC(50)=28 nM), which is efficacious in reduction of Abeta production in vivo.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Secretases da Proteína Precursora do Amiloide/antagonistas & inibidores , Isoleucina/análogos & derivados , Receptor Notch1/metabolismo , Álcoois , Secretases da Proteína Precursora do Amiloide/metabolismo , Precursor de Proteína beta-Amiloide/química , Animais , Desenho de Fármacos , Humanos , Isoleucina/química , Modelos Químicos , Propanolaminas/química , Sulfonamidas/químicaRESUMO
Alpha 7 nicotinic acetylcholine receptor (alpha(7) nAChR) agonists are promising therapeutic candidates for the treatment of cognitive impairment associated with a variety of disorders including Alzheimer's disease and schizophrenia. Alpha 7 nAChRs are expressed in brain regions associated with cognitive function, regulate cholinergic neurotransmission and have been shown to be down regulated in both schizophrenia and Alzheimer's disease. Herein we report a novel, potent small molecule agonist of the alpha 7 nAChR, SEN12333/WAY-317538. This compound is a selective agonist of the alpha(7) nAChR with excellent in vitro and in vivo profiles, excellent brain penetration and oral bioavailability, and demonstrates in vivo efficacy in multiple behavioural cognition models. The SAR and biological evaluation of this series of compounds are discussed.
Assuntos
Morfolinas/química , Morfolinas/farmacologia , Agonistas Nicotínicos/química , Agonistas Nicotínicos/farmacologia , Piridinas/química , Piridinas/farmacologia , Receptores Nicotínicos/metabolismo , Doença de Alzheimer/tratamento farmacológico , Animais , Ligação Competitiva , Cálcio/metabolismo , Linhagem Celular , Cognição/efeitos dos fármacos , Eletrofisiologia , Humanos , Morfolinas/farmacocinética , Agonistas Nicotínicos/farmacocinética , Piridinas/farmacocinética , Ratos , Ratos Wistar , Esquizofrenia/tratamento farmacológico , Relação Estrutura-Atividade , Receptor Nicotínico de Acetilcolina alfa7RESUMO
5-Hydroxytryptamine (5-HT)(1A) receptors play an important role in multiple cognitive processes, and compelling evidence suggests that 5-HT(1A) antagonists can reverse cognitive impairment. We have examined the therapeutic potential of a potent (K(i) = 1.1 nM), selective (>100-fold), orally bioavailable, silent 5-HT(1A) receptor antagonist (K(B) = 1.3 nM) (R)-N-(2-methyl-(4-indolyl-1-piperazinyl)-ethyl)-N-(2-pyridinyl)-cyclohexane carboxamide (WAY-101405). Oral administration of WAY-101405 was shown to be effective in multiple rodent models of learning and memory. In a novel object recognition paradigm, 1 mg/kg enhanced retention (memory) for previously learned information, and it was able to reverse the memory deficits induced by scopolamine. WAY-101405 (1 mg/kg) was also able to reverse scopolamine-induced deficits in a rat contextual fear conditioning model. In the Morris water maze, WAY-101405 (3 mg/kg) significantly improved learning in a paradigm of increasing task difficulty. In vivo microdialysis studies in the dorsal hippocampus of freely moving adult rats demonstrated that acute administration of WAY-101405 (10 mg/kg) increased extracellular acetylcholine levels. The selective radioligand [(3)H]WAY-100635, administered i.v., was used for in vivo receptor occupancy studies, where WAY-101405 occupied 5-HT(1A) receptors in the rat cortex, with an ED(50) value of 0.1 mg/kg p.o. Taken together, these studies demonstrate that WAY-101405 is a potent and selective, brain penetrant, orally bioavailable 5-HT(1A) receptor "silent" antagonist that is effective in preclinical memory paradigms at doses where approximately 90% of the postsynaptic 5-HT(1A) receptors are occupied. These results further support the rationale for use of this compound class in the treatment of cognitive dysfunction associated with psychiatric and neurological conditions.
Assuntos
Aminopiridinas/farmacologia , Cognição/efeitos dos fármacos , Cicloexanos/farmacologia , Piperazinas/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina , Antagonistas da Serotonina/farmacologia , Animais , Disponibilidade Biológica , Encéfalo/metabolismo , Memória/efeitos dos fármacos , Modelos Animais , Ensaio Radioligante , Ratos , Antagonistas da Serotonina/administração & dosagem , Antagonistas da Serotonina/farmacocinéticaRESUMO
Increased impulsivity is observed across a number of neuropsychiatric and neurodegenerative diseases. Preclinical evidence has demonstrated that antagonism of the serotonin 5-HT(2C) receptor may act to increase impulsivity, leading to the hypothesis that an agonist may exert reciprocal effects and attenuate impulsive behavior. The 5-HT(2C) agonist, WAY-163909, was evaluated in the present paper using a variable stimulus duration and inter-trial interval manipulation in the 5-choice serial reaction time test designed to increase impulsivity and decrease attention. WAY-163909 treatment selectively and dose-dependently decreased impulsivity suggesting that agonism of the 5-HT(2C) receptor may be useful for modulating impulsivity in disease states where impulsivity is a pathological feature.