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1.
J Pharmacol Exp Ther ; 374(1): 113-125, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32358046

RESUMO

IRL790 ([2-(3-fluoro-5-methanesulfonylphenoxy)ethyl](propyl)amine, mesdopetam) is a novel compound in development for the clinical management of motor and psychiatric disabilities in Parkinson disease. The discovery of IRL790 was made applying a systems pharmacology approach based on in vivo response profiling. The chemical design idea was to develop a new type of DA D3/D2 receptor type antagonist built on agonist rather than antagonist structural motifs. We hypothesized that such a dopamine antagonist with physicochemical properties similar to agonists would exert antidyskinetic and antipsychotic effects in states of dysregulated dopaminergic signaling while having little negative impact on physiologic dopamine transmission and, hence, minimal liability for side effects related to dopamine-dependent functions. At the level of in vivo pharmacology, IRL790 displays balancing effects on aberrant motor phenotypes, reducing l-DOPA-induced dyskinesias in the rodent 6-hydroxydopamine lesion model and reducing psychostimulant-induced locomotor hyperactivity elicited by pretreatment with either d-amphetamine or dizocilpine, without negatively impacting normal motor performance. Thus, IRL790 has the ability to normalize the behavioral phenotype in hyperdopaminergic as well as hypoglutamatergic states. Neurochemical and immediate early gene (IEG) response profiles suggest modulation of DA neurotransmission, with some features, such as increased DA metabolites and extracellular DA, shared by atypical antipsychotics and others, such as increased frontal cortex IEGs, unique to IRL790. IRL790 also increases extracellular levels of acetylcholine in the prefrontal cortex and ventral hippocampus. At the receptor level, IRL790 appears to act as a preferential DA D3 receptor antagonist. Computational docking studies support preferential affinity at D3 receptors with an agonist-like binding mode. SIGNIFICANCE STATEMENT: This paper reports preclinical pharmacology along with molecular modeling results on IRL790, a novel compound in clinical development for the treatment of motor and psychiatric complications in advanced Parkinson disease. IRL790 is active in models of perturbed dopaminergic and glutamatergic signaling, including rodent 6-hydroxydopamine l-DOPA-induced dyskinesias and psychostimulant-induced hyperactivity, in a dose range that does not impair normal behavior. This effect profile is attributed to interactions at dopamine D2/D3 receptors, with a 6- to 8-fold preference for the D3 subtype.


Assuntos
Dopamina/metabolismo , Transtornos Mentais/complicações , Transtornos Motores/complicações , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Masculino , Simulação de Acoplamento Molecular , Doença de Parkinson/complicações , Conformação Proteica , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D3/química , Receptores de Dopamina D3/metabolismo
2.
ACS Chem Neurosci ; 8(4): 785-797, 2017 04 19.
Artigo em Inglês | MEDLINE | ID: mdl-27997108

RESUMO

This paper describes the application of in vivo systems response profiling in CNS drug discovery by a process referred to as the Integrative Screening Process. The biological response profile, treated as an array, is used as major outcome for selection of candidate drugs. Dose-response data, including ex vivo brain monoaminergic biomarkers and behavioral descriptors, are systematically collected and analyzed by principal component analysis (PCA) and partial least-squares (PLS) regression, yielding multivariate characterization across compounds. The approach is exemplified by assessing a new class of CNS active compounds, the dopidines, compared to other monoamine modulating compounds including antipsychotics, antidepressants, and procognitive agents. Dopidines display a distinct phenotypic profile which has prompted extensive further preclinical and clinical investigations. In summary, in vivo profiles of CNS compounds are mapped, based on dose response studies in the rat. Applying a systematic and standardized work-flow, a database of in vivo systems response profiles is compiled, enabling comparisons and classification. This creates a framework for translational mapping, a crucial component in CNS drug discovery.


Assuntos
Fármacos do Sistema Nervoso Central/farmacologia , Avaliação Pré-Clínica de Medicamentos/métodos , Animais , Análise dos Mínimos Quadrados , Masculino , Ratos , Ratos Sprague-Dawley
3.
J Neurosci Methods ; 234: 38-53, 2014 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-25020253

RESUMO

BACKGROUND: The need for improving throughput, validity, and reliability in the behavioral characterization of rodents may benefit from integrating automated intra-home-cage-screening systems allowing the simultaneous detection of multiple behavioral and physiological parameters in parallel. NEW METHOD: To test this hypothesis, transgenic Huntington's disease (tgHD) rats were repeatedly screened within phenotyping home-cages (PhenoMaster and IntelliCage for rats), where spontaneous activity, feeding, drinking, temperature, and metabolic performance were continuously measured. Cognition and emotionality were evaluated within the same environment by means of operant learning procedures and refined analysis of the behavioral display under conditions of novelty. This investigator-independent approach was further correlated with behavioral display of the animals in classical behavioral assays. Multivariate analysis (MVA) including Principle Component Analysis (PCA) and Partial Least Squares Discriminant Analysis (PLS-DA) was used to explore correlation patterns of variables within and across the two genotypes. RESULTS: The automated systems traced previously undetected aspects in the phenotype of tgHD rats (circadian activity, energy metabolism, rearing), and out of those spontaneous free rearing correlated with individual performance in the accelerod test. PCA revealed a segregation by genotype in juvenile tgHD rats that differed from adult animals, being further resolved by PLS-DA detecting "temperature" (juvenile) and "rearing" (adult) as phenotypic key variables in the tgHD model. CONCLUSIONS: Intra-home-cage phenotyping in combination with MVA, is capable of characterizing a complex phenotype by detecting novel physiological and behavioral markers with high sensitivity and standardization using fewer human resources. A broader application of automated systems for large-scale screening is encouraged.


Assuntos
Mineração de Dados , Processamento Eletrônico de Dados , Doença de Huntington , Monitorização Fisiológica/métodos , Fenótipo , Animais , Análise Discriminante , Modelos Animais de Doenças , Proteína Huntingtina , Doença de Huntington/complicações , Doença de Huntington/diagnóstico , Doença de Huntington/genética , Monitorização Fisiológica/instrumentação , Análise Multivariada , Mutação/genética , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Ratos , Ratos Sprague-Dawley , Ratos Transgênicos
4.
Eur J Pharmacol ; 698(1-3): 278-85, 2013 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-23127496

RESUMO

Treatment-limiting motor complications occur in patients with Parkinson's disease after chronic levodopa (L-DOPA) treatment, and represent an unmet medical need. We examined the motor and neurochemical effects of the dopaminergic stabilizer pridopidine (NeuroSearch A/S, Ballerup, Denmark) in the unilateral rodent 6-OHDA lesion model, which is often used to evaluate the potential of experimental compounds for such dopamine-related motor complications. In total, 72 rats were hemi-lesioned and allocated to receive twice-daily injections of either vehicle; 6.5mg/kg L-DOPA; L-DOPA + 25 µmol/kg pridopidine; or L-DOPA + 25 µmol/kg (-)-OSU6162-a prototype dopaminergic stabilizer used previously in 6-OHDA hemi-lesion models. Animals were treated for 7, 14 or 21 days, and locomotor activity and ex vivo brain tissue neurochemistry analysed. In agreement with previous studies, L-DOPA sensitised the motor response, producing significantly more contralateral rotations than vehicle (P<0.05). Concomitant administration of pridopidine and L-DOPA significantly decreased the number of L-DOPA-induced contralateral rotations on day 7, 14 and 21 (P<0.05 versus L-DOPA alone), while still allowing a beneficial locomotor stimulant effect of L-DOPA. Concomitant pridopidine also reduced L-DOPA-induced rotation asymmetry (P<0.05 versus L-DOPA alone) and had no adverse effects on distance travelled. Brain neurochemistry was generally unaffected in all treatments groups. In conclusion, pridopidine shows potential for reducing motor complications of L-DOPA in Parkinson's disease and further testing is warranted.


Assuntos
Sensibilização do Sistema Nervoso Central/efeitos dos fármacos , Dopamina/metabolismo , Levodopa/farmacologia , Locomoção/efeitos dos fármacos , Locomoção/fisiologia , Oxidopamina/farmacologia , Piperidinas/farmacologia , Animais , Dopaminérgicos/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Rotação , Fatores de Tempo
5.
Clin Neuropharmacol ; 34(3): 95-100, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21586914

RESUMO

OBJECTIVES: Huntington disease is a hereditary neurodegenerative disorder resulting in loss of motor, cognitive, and behavioral functions and is characterized by a distinctive pattern of cerebral metabolic abnormalities. Pridopidine (ACR16) belongs to a novel class of central nervous system compounds in development for the treatment of Huntington disease. The objective of the study was to investigate the metabolic changes in patients with Huntington disease before and after pridopidine treatment. METHODS: [(18)F]Fluorodeoxyglucose positron emission tomographic imaging was used to measure the regional cerebral metabolic rate of glucose at baseline and after 14 days of open-label pridopidine treatment in 8 patients with Huntington disease. Clinical assessments were performed using the Unified Huntington's Disease Rating Scale. RESULTS: Statistical parametric mapping analysis showed increased metabolic activity in several brain regions such as the precuneus and the mediodorsal thalamic nucleus after treatment. In addition, after pridopidine treatment, the correlation between the clinical status and the cerebral metabolic activity was strengthened. CONCLUSIONS: Our findings suggest that pridopidine induces metabolic changes in brain regions implicated as important for mediating compensatory mechanisms in Huntington disease. In addition, the finding of a strong relationship between clinical severity and metabolic activity after treatment also suggests that pridopidine treatment targets a Huntington disease-related metabolic activity pattern.


Assuntos
Encéfalo/metabolismo , Glucose/metabolismo , Doença de Huntington/tratamento farmacológico , Doença de Huntington/metabolismo , Piperidinas/metabolismo , Piperidinas/uso terapêutico , Adulto , Idoso , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Feminino , Humanos , Doença de Huntington/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Piperidinas/farmacologia , Tomografia por Emissão de Pósitrons/métodos , Resultado do Tratamento
6.
Eur J Pharmacol ; 644(1-3): 88-95, 2010 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-20667452

RESUMO

Pridopidine (ACR16) belongs to a new pharmacological class of agents affecting the central nervous system called dopaminergic stabilizers. Dopaminergic stabilizers act primarily at dopamine type 2 (D(2)) receptors and display state-dependent behavioural effects. This article aims to give an overview of the preclinical neurochemical and behavioural in vivo pharmacological properties of pridopidine. Pridopidine was given s.c. to male Sprague-Dawley rats (locomotor, microdialysis and tissue neurochemistry) and i.p. to Swiss male mice (tail suspension test). Pridopidine dose-dependently increased striatal tissue levels of the dopamine metabolite 3,4-dihydroxyphenylalanin (ED(50)=81 micromol/kg), and prefrontal cortex dialysate levels of dopamine and noradrenaline as measured by high performance liquid chromatography. The agent reduced hyperlocomotion (d-amphetamine: ED(50)=54 micromol/kg; MK-801: ED(50)=40 micromol/kg), but preserved spontaneous locomotor activity, confirming state-dependent behavioural effects. In addition, pridopidine significantly reduced immobility time in the tail suspension test. We conclude that pridopidine state-dependently stabilizes psychomotor activity by the dual actions of functional dopamine D(2) receptor antagonism and strengthening of cortical glutamate functions in various settings of perturbed neurotransmission. The putative restoration of function in cortico-subcortical circuitry by pridopidine is likely to make it useful for ameliorating several neurological and psychiatric disorders, including Huntington's disease.


Assuntos
Di-Hidroxifenilalanina/efeitos dos fármacos , Antagonistas dos Receptores de Dopamina D2 , Dopamina/metabolismo , Piperidinas/farmacologia , Animais , Cromatografia Líquida de Alta Pressão , Di-Hidroxifenilalanina/metabolismo , Relação Dose-Resposta a Droga , Injeções Subcutâneas , Masculino , Camundongos , Microdiálise , Atividade Motora/efeitos dos fármacos , Norepinefrina/metabolismo , Piperidinas/administração & dosagem , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Dopamina D2/metabolismo
7.
Eur Neuropsychopharmacol ; 12(4): 327-36, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12126872

RESUMO

Patients with chronic hepatic encephalopathy (HE) may present affective symptoms and antidepressant drug treatment in this condition is not uncommon. The present microdialysis study investigated treatment with the chronic antidepressant venlafaxine (VEN) in experimental HE with regard to tentative changes in pharmacokinetic and/or pharmacodynamic parameters. Three weeks after portacaval shunt (PCS) or sham operation in rats, VEN (10 mg/kg daily) was administered by implanted osmotic minipumps. VEN treatment for 14 days resulted in higher concentrations of VEN in PCS rats than in sham controls in serum and brain compartments, and the VEN levels in serum and brain were strongly inter-correlated. The serum N-desmethylvenlafaxine concentration did not differ between the groups, but correlated with the serum VEN levels. The other VEN metabolites were below the quantification limits. VEN treatment for 9-12 days significantly stimulated locomotion and rearing in the open field in sham controls, but failed to do so in the PCS rats. The concentrations of noradrenaline, dopamine, 5-HT, and 5-HIAA in neocortical dialysates were higher in PCS than in sham rats after 14 days of VEN treatment, but the elevations reached statistical significance only in the case of dopamine and 5-HIAA. In summary, there were significant pharmacokinetic and pharmacodynamic alterations in rats with experimental HE as compared to controls. The described experimental HE model may be useful for continued pharmacokinetic/pharmacodynamic interaction studies to unravel the pathophysiological consequences of HE on the CNS.


Assuntos
Comportamento Animal/efeitos dos fármacos , Monoaminas Biogênicas/metabolismo , Encéfalo/efeitos dos fármacos , Cicloexanóis/farmacologia , Inibidores Enzimáticos/farmacologia , Encefalopatia Hepática/metabolismo , Análise de Variância , Animais , Encéfalo/metabolismo , Cicloexanóis/sangue , Cicloexanóis/farmacocinética , Soluções para Diálise/análise , Soluções para Diálise/metabolismo , Modelos Animais de Doenças , Inibidores Enzimáticos/farmacocinética , Encefalopatia Hepática/tratamento farmacológico , Encefalopatia Hepática/fisiopatologia , Masculino , Microdiálise , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Cloridrato de Venlafaxina
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