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1.
Eur J Pharmacol ; 890: 173635, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-33065094

RESUMO

F17464 (N-(3-{4-[4-(8-Oxo-8H-[1,3]-dioxolo-[4,5-g]-chromen-7-yl)-butyl]-piperazin-1-yl}-phenyl)-methanesulfonamide, hydrochloride) is a new potential antipsychotic with a unique profile. The compound exhibits high affinity for the human dopamine receptor subtype 3 (hD3) (Ki = 0.17 nM) and the serotonin receptor subtype 1a (5-HT1a) (Ki = 0.16 nM) and a >50 fold lower affinity for the human dopamine receptor subtype 2 short and long form (hD2s/l) (Ki = 8.9 and 12.1 nM, respectively). [14C]F17464 dynamic studies show a slower dissociation rate from hD3 receptor (t1/2 = 110 min) than from hD2s receptor (t1/2 = 1.4 min) and functional studies demonstrate that F17464 is a D3 receptor antagonist, 5-HT1a receptor partial agonist. In human dopaminergic neurons F17464 blocks ketamine induced morphological changes, an effect D3 receptor mediated. In vivo F17464 target engagement of both D2 and 5-HT1a receptors is demonstrated in displacement studies in the mouse brain. F17464 increases dopamine release in the rat prefrontal cortex and mouse lateral forebrain - dorsal striatum and seems to reduce the effect of MK801 on % c-fos mRNA medium expressing neurons in cortical and subcortical regions. F17464 also rescues valproate induced impairment in a rat social interaction model of autism. All the neurochemistry and behavioural effects of F17464 are observed in the dose range 0.32-2.5 mg/kg i.p. in both rats and mice. The in vitro - in vivo pharmacology profile of F17464 in preclinical models is discussed in support of a therapeutic use of the compound in schizophrenia and autism.


Assuntos
Antipsicóticos/farmacologia , Benzopiranos/farmacologia , Antagonistas de Dopamina/farmacologia , Piperazinas/farmacologia , Receptores de Dopamina D3/antagonistas & inibidores , Sulfonamidas/farmacologia , Animais , Antipsicóticos/uso terapêutico , Transtorno Autístico/induzido quimicamente , Transtorno Autístico/tratamento farmacológico , Comportamento Animal/efeitos dos fármacos , Benzopiranos/uso terapêutico , Monoaminas Biogênicas/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Catalepsia/tratamento farmacológico , Células Cultivadas , Dopamina/metabolismo , Antagonistas de Dopamina/uso terapêutico , Neurônios Dopaminérgicos/efeitos dos fármacos , Feminino , Genes fos/efeitos dos fármacos , Masculino , Camundongos , Plasticidade Neuronal/efeitos dos fármacos , Piperazinas/uso terapêutico , Prolactina/sangue , Ratos Sprague-Dawley , Receptores de Dopamina D3/metabolismo , Sulfonamidas/uso terapêutico , Ácido Valproico/toxicidade
2.
J Pharmacol Toxicol Methods ; 64(1): 74-80, 2011.
Artigo em Inglês | MEDLINE | ID: mdl-21406241

RESUMO

INTRODUCTION: General neurobehavioral assays, like a modified Irwin test or a functional observational battery, are necessary for central nervous system (CNS) safety pharmacology testing near the end of the target validation (early discovery) stage of preclinical drug development. However, at earlier stages, when a greater number of test compounds must be screened for potential CNS side effects, locomotor activity assessment may be a better tool for the comparison of compounds. METHODS: Spontaneous locomotor activity counts obtained from two automated test systems - an infrared beam-based activity meter (Actimeter) and the mechanical vibration-based LABORAS - were compared in rats dosed with chlorpromazine (2-8mg/kg) or caffeine (3-24mg/kg), p.o. A modified Irwin test was also performed to visually observe the neurobehavioral effects. RESULTS: In all three assays, dose-dependent sedation- and excitation-related effects were observed with chlorpromazine and caffeine, respectively. The two automated activity-detection systems exhibited similar sensitivities in determining changes in locomotor activity, but with the LABORAS being more sensitive than the Actimeter in detecting caffeine-induced increases in vertical activity (rearing behavior). DISCUSSION: Infrared beam-based activity detection systems and LABORAS provide relatively-comparable quantitative data regarding locomotor activity. Practical considerations, such as relative cost versus degree of versatility, should be considered when deciding which system to use for the screening of test compounds during the earliest stages of preclinical drug development.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Atividade Motora/efeitos dos fármacos , Testes de Toxicidade/métodos , Animais , Cafeína/farmacologia , Cafeína/toxicidade , Clorpromazina/farmacologia , Clorpromazina/toxicidade , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Masculino , Ratos , Ratos Wistar
3.
J Pharmacol Exp Ther ; 333(3): 632-8, 2010 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-20200119

RESUMO

Schizophrenia is characterized by three major symptom classes: positive symptoms, negative symptoms, and cognitive deficits. Classical antipsychotics (phenothiazines, thioxanthenes, and butyrophenones) are effective against positive symptoms but induce major side effects, in particular, extrapyramidal symptoms (EPS). The discovery of clozapine, which does not induce EPS and is thought effective against all three classes of symptom, has driven research for novel antipsychotics with a wider activity spectrum and lower EPS liability. To increase predictiveness, current efforts aim to develop translational models where direct parallels can be drawn between the processes studied in animals and in humans. The present article reviews existing procedures in animals for their ability to predict compound efficacy and EPS liability in relation to their translational validity. Rodent models of positive symptoms include procedures related to dysfunction in central dopamine and glutamatergic (N-methyl-D-aspartate) and serotonin (5-hydroxytryptamine) neurotransmission. Procedures for evaluating negative symptoms include rodent models of anhedonia, affective flattening, and diminished social interaction. Cognitive deficits can be assessed in rodent models of attention (prepulse inhibition) and of learning/memory (object and social recognition, Morris water maze and operant-delayed alternation). The relevance of the conditioned avoidance response is also discussed. A final section reviews procedures for assessing EPS liability, in particular, parkinsonism (catalepsy in rodents), acute dystonia (purposeless chewing in rodents, dystonia in monkeys), akathisia (defecation in rodents), and tardive dyskinesia (long-term antipsychotic treatment in rodents and monkeys). It is concluded that, with notable exceptions (attention, learning/memory, EPS liability), current predictive models for antipsychotics fall short of clear translational validity.


Assuntos
Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Comportamento/efeitos dos fármacos , Descoberta de Drogas , Animais , Antipsicóticos/efeitos adversos , Antipsicóticos/uso terapêutico , Transtornos Cognitivos/diagnóstico , Transtornos Cognitivos/psicologia , Discinesia Induzida por Medicamentos/diagnóstico , Discinesia Induzida por Medicamentos/psicologia , Humanos , Transtornos Psicóticos/psicologia
4.
Adv Pharmacol ; 57: 381-418, 2009.
Artigo em Inglês | MEDLINE | ID: mdl-20230767

RESUMO

Schizophrenia is a major psychiatric disease that is characterized by three distinct symptom domains: positive symptoms, negative symptoms, and cognitive impairment. Additionally, treatment with classical antipsychotic medication can be accompanied by important side effects that involve extrapyramidal symptoms (EPS). The discovery of clozapine in the 1970s, which is efficacious in all three symptom domains and has a reduced propensity to induce EPS, has driven research for new antipsychotic agents with a wider spectrum of activity and a lower propensity to induce EPS. The following chapter reviews existing behavioral procedures in animals for their ability to predict compound efficacy against schizophrenia symptoms and liability to induce EPS. Rodent models of positive symptoms include procedures related to hyperfunction in central dopamine and serotonin (5-hydroxytryptamine) systems and hypofunction of central glutamatergic (N-methyl-d-aspartate) neurotransmission. Procedures for evaluating negative symptoms include rodent models of anhedonia, affective flattening, and diminished social interaction. Cognitive deficits can be assessed in rodent models of attention (prepulse inhibition (PPI), latent inhibition) and of learning and memory (passive avoidance, object and social recognition, Morris water maze, and operant-delayed alternation). The relevance of the conditioned avoidance response (CAR) is also discussed. A final section reviews animal procedures for assessing EPS liability, in particular parkinsonism (catalepsy), acute dystonia (purposeless chewing in rodents, dystonia in monkeys), akathisia (defecation in rodents), and tardive dyskinesia (long-term antipsychotic treatment in rodents and monkeys).


Assuntos
Antipsicóticos/farmacologia , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Animais , Cognição/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Humanos
5.
J Pharmacol Exp Ther ; 302(2): 731-41, 2002 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-12130738

RESUMO

SL65.0155 [5-(8-amino-7-chloro-2,3-dihydro-1,4-benzodioxin-5-yl)-3-[1-(2-phenyl ethyl)-4-piperidinyl]-1,3,4-oxadiazol-2(3H)-one monohydrochloride] is a novel benzodioxanoxadiazolone compound with high affinity for human 5-hydroxytryptamine (5-HT)(4) receptors (K(i) of 0.6 nM) and good selectivity (greater than 100-fold for all other receptors tested). In cells expressing the 5-HT(4(b)) and 5-HT(4(e)) splice variants, SL65.0155 acted as a partial agonist, stimulating cAMP production with a maximal effect of 40 to 50% of serotonin. However, in the rat esophagus preparation, SL65.0155 acted as a 5-HT(4) antagonist with a pK(b) of 8.81. In addition, SL65.0155 potently improved performance in several tests of learning and memory. In the object recognition task, it improved retention at 24 h when administered i.p. or p.o. (0.001-0.1 mg/kg). This effect was antagonized by the 5-HT(4) antagonist SDZ 205,557, itself without effect, demonstrating that the promnesic effects of SL65.0155 are mediated by 5-HT(4) agonism. SL65.0155 also reversed the cognitive deficits of aged rats in the linear maze task and the scopolamine-induced deficit of mice in the water maze task. Furthermore, the combined administration of an inactive dose of SL65.0155 with the cholinesterase inhibitor rivastigmine resulted in a significant promnesic effect, suggesting a synergistic interaction. SL65.0155 was devoid of unwanted cardiovascular, gastrointestinal, or central nervous system effects with doses up to more than 100-fold higher than those active in the cognitive tests. These results characterize SL65.0155 as a novel promnesic agent acting via 5-HT(4) receptors, with an excellent preclinical profile. Its broad range of activity in cognitive tests and synergism with cholinesterase inhibitors suggest that SL65.0155 represents a promising new agent for the treatment of dementia.


Assuntos
Cognição/fisiologia , AMP Cíclico/metabolismo , Dioxanos/farmacologia , Aprendizagem em Labirinto/fisiologia , Oxidiazóis/farmacologia , Receptores de Serotonina/fisiologia , Agonistas do Receptor de Serotonina/farmacologia , Processamento Alternativo , Animais , Pressão Sanguínea/efeitos dos fármacos , Células CHO , Células COS , Chlorocebus aethiops , Cognição/efeitos dos fármacos , Cricetinae , Esôfago/efeitos dos fármacos , Esôfago/fisiologia , Motilidade Gastrointestinal/efeitos dos fármacos , Cobaias , Frequência Cardíaca/efeitos dos fármacos , Íleo/efeitos dos fármacos , Íleo/fisiologia , Aprendizagem em Labirinto/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Ensaio Radioligante , Ratos , Receptores de Serotonina/efeitos dos fármacos , Receptores de Serotonina/genética , Receptores 5-HT4 de Serotonina , Proteínas Recombinantes/efeitos dos fármacos , Proteínas Recombinantes/metabolismo , Transfecção
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