Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 20
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Neuropharmacology ; 66: 202-14, 2013 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-22551786

RESUMO

Evidence suggests that 30-50% of patients suffering from major depressive disorder (MDD) are classified as suffering from treatment resistant depression (TRD) as they have an inadequate response to standard antidepressants. A key feature of this patient population is the increased incidence of co-morbid symptoms like anxiety and pain. Recognizing that current standards of care are largely focused on monoaminergic mechanisms of action (MOAs), innovative approaches to drug discovery for TRD are targeting glutamate hyperfunction. Here we describe the in vitro and in vivo profile of GRN-529, a novel negative allosteric modulator (NAM) of metabotropic glutamate receptor 5 (mGluR5). In cell based pharmacology assays, GRN-529 is a high affinity (Ki 5.4 nM), potent (IC50 3.1 nM) and selective (>1000-fold selective vs mGluR1) mGluR5 NAM. Acute administration of GRN-529 (0.1-30 mg/kg p.o.) had dose-dependent efficacy across a therapeutically relevant battery of animal models, comprising depression (decreased immobility time in tail suspension and forced swim tests) and 2 of the co-morbid symptoms overrepresented in TRD, namely anxiety (attenuation of stress-induced hyperthermia, and increased punished crossings in the four plate test) and pain (reversal of hyperalgesia due to sciatic nerve ligation or inflammation). The potential side effect liability of GRN-529 was also assessed using preclinical models: GRN-529 had no effect on rat sexual behavior or motor co-ordination (rotarod), however it impaired cognition in mice (social odor recognition). Efficacy and side effects of GRN-529 were compared to standard of care agents (antidepressant, anxiolytic or analgesics) and the tool mGluR5 NAM, MTEP. To assess the relationship between target occupancy and efficacy, ex vivo receptor occupancy was measured in parallel with efficacy testing. This revealed a strong correlation between target engagement, exposure and efficacy across behavioral endpoints, which supports the potential translational value of PET imaging to dose selection in patients. Collectively this broad spectrum profile of efficacy of GRN-529 supports our hypothesis that negative allosteric modulation of mGluR5 could represent an innovative therapeutic approach to the treatment of TRD. This article is part of a Special Issue entitled 'Metabotropic Glutamate Receptors'.


Assuntos
Regulação Alostérica/efeitos dos fármacos , Transtorno Depressivo Resistente a Tratamento/tratamento farmacológico , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Regulação Alostérica/fisiologia , Analgésicos/farmacologia , Animais , Ansiolíticos/farmacologia , Antidepressivos/efeitos adversos , Antidepressivos/farmacologia , Antidepressivos/uso terapêutico , Comportamento Animal/efeitos dos fármacos , Benzamidas/efeitos adversos , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Cálcio/metabolismo , Transtorno Depressivo Resistente a Tratamento/metabolismo , Transtorno Depressivo Resistente a Tratamento/fisiopatologia , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Avaliação Pré-Clínica de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos/psicologia , Antagonistas de Aminoácidos Excitatórios/efeitos adversos , Antagonistas de Aminoácidos Excitatórios/farmacologia , Ácido Glutâmico/farmacologia , Células HEK293 , Humanos , Camundongos , Piridinas/efeitos adversos , Piridinas/farmacologia , Piridinas/uso terapêutico , Ensaio Radioligante/métodos , Ratos , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/metabolismo , Receptores de Glutamato Metabotrópico/fisiologia
2.
Br J Pharmacol ; 157(2): 307-19, 2009 May.
Artigo em Inglês | MEDLINE | ID: mdl-19338583

RESUMO

BACKGROUND AND PURPOSE: As a combination of 5-HT selective reuptake inhibitor (SSRI) with 5-HT(1A) receptor antagonism may yield a rapidly acting antidepressant, WAY-211612, a compound with both SSRI and 5-HT(1A) receptor antagonist activities, was evaluated in preclinical models. EXPERIMENTAL APPROACH: Occupancy studies confirmed the mechanism of action of WAY-211612, while its in vivo profile was characterized in microdialysis and behavioural models. KEY RESULTS: WAY-211612 inhibited 5-HT reuptake (K(i) = 1.5 nmol.L(-1); K(B) = 17.7 nmol.L(-1)) and exhibited full 5-HT(1A) receptor antagonist activity (K(i) = 1.2 nmol.L(-1); K(B) = 6.3 nmol.L(-1); I(max) 100% in adenyl cyclase assays; K(B) = 19.8 nmol.L(-1); I(max) 100% in GTPgammaS). WAY-211612 (3 and 30 mg.kg(-1), po) occupied 5-HT reuptake sites in rat prefrontal cortex (56.6% and 73.6% respectively) and hippocampus (52.2% and 78.5%), and 5-HT(1A) receptors in the prefrontal cortex (6.7% and 44.7%), hippocampus (8.3% and 48.6%) and dorsal raphe (15% and 83%). Acute or chronic treatment with WAY-211612 (3-30 mg.kg(-1), po) raised levels of cortical 5-HT approximately twofold, as also observed with a combination of an SSRI (fluoxetine; 30 mg.kg(-1), s.c.) and a 5-HT(1A) antagonist (WAY-100635; 0.3 mg.kg(-1), s.c). WAY-211612 (3.3-30 mg.kg(-1), s.c.) decreased aggressive behaviour in the resident-intruder model, while increasing the number of punished crossings (3-30 mg.kg(-1), i.p. and 10-56 mg.kg(-1), po) in the mouse four-plate model and decreased adjunctive drinking behaviour (56 mg.kg(-1), i.p.) in the rat scheduled-induced polydipsia model. CONCLUSIONS AND IMPLICATIONS: These findings suggest that WAY-211612 may represent a novel antidepressant.


Assuntos
Antidepressivos de Segunda Geração/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Antagonistas do Receptor 5-HT1 de Serotonina , Antagonistas da Serotonina/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Cromatografia Líquida de Alta Pressão , AMP Cíclico/metabolismo , Masculino , Camundongos , Microdiálise , Ratos , Ratos Sprague-Dawley
3.
Bioorg Med Chem Lett ; 11(14): 1885-8, 2001 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-11459653
5.
Bioorg Med Chem Lett ; 9(17): 2593-8, 1999 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-10498215

RESUMO

The synthesis of several bioisosteric analogs based on the 3-OH-phenoxyethylamine dopamine D2 agonist template (i.e., 3) is described. The benzimidazol-2-ones and benzthioimidazol-2-ones (7-10) and 2-trifluoromethyl-benzimidazole (13) were observed to have excellent affinity for the D2 receptor.


Assuntos
Benzimidazóis/síntese química , Dopaminérgicos/síntese química , Receptores de Dopamina D2/efeitos dos fármacos , Animais , Benzimidazóis/química , Benzimidazóis/farmacologia , Dopaminérgicos/química , Dopaminérgicos/farmacologia , Camundongos , Atividade Motora/efeitos dos fármacos
6.
J Med Chem ; 42(11): 2007-20, 1999 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-10354409

RESUMO

A series of 4-(aminoethoxy)indoles 7 and a related series of 4-(aminoethoxy)indolones 8 were synthesized and evaluated for their affinity for both the high- and low-affinity agonist states (D2High and D2Low, respectively) of the dopamine (DA) D2 receptor. The 4-aminoethoxy derivatives (i.e., 7 and 8) were designed as bioisosteric analogues based on the phenol prototype 4. The indolones 8 were observed to have high affinity for the D2High receptor. Comparison of their previously reported chroman analogues with the more flexible 4-(aminoethoxy)indoles revealed the chroman analogues to be more potent, whereas little loss in D2High affinity was observed when comparing the 4-(aminoethoxy)indolones with their respective chroman analogues. Several regions of the phenoxyethylamine framework were modified and recognized as potential sites to modulate the level of intrinsic activity. A conformational analysis was performed and a putative bioactive conformation was proposed which fulfilled the D2 agonist pharmacophore criteria based on the McDermed model. Structure-activity relationships gained from these studies have aided in the synthesis of D2 partial agonists of varying intrinsic activity levels. These agents should be of therapeutic value in treating disorders resulting from hypo- and hyperdopaminergic activity, without the side effects associated with complete D2 agonism or antagonism.


Assuntos
Agonistas de Dopamina/química , Etilaminas/química , Indóis/química , Receptores de Dopamina D2/metabolismo , Animais , Ligação Competitiva , Corpo Estriado/metabolismo , Agonistas de Dopamina/síntese química , Agonistas de Dopamina/metabolismo , Agonistas de Dopamina/farmacologia , Etilaminas/síntese química , Etilaminas/metabolismo , Etilaminas/farmacologia , Hipocampo/metabolismo , Técnicas In Vitro , Indóis/síntese química , Indóis/metabolismo , Indóis/farmacologia , Camundongos , Modelos Moleculares , Conformação Molecular , Atividade Motora/efeitos dos fármacos , Ensaio Radioligante , Ratos , Comportamento Estereotipado/efeitos dos fármacos , Relação Estrutura-Atividade
7.
Bioorg Med Chem Lett ; 8(3): 295-300, 1998 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-9871673

RESUMO

Described in this report is a systematic study which led to the identification of two new dopamine D2 partial agonists (5 and 17). Phenols 5 and 17 represent prototypes of two new classes of D2 partial agonists as well as templates for the future design of novel dopaminergic agents.


Assuntos
Agonistas de Dopamina/química , Fenóis/química , Piperazinas/química , Agonistas de Dopamina/farmacologia , Fenóis/síntese química , Fenóis/farmacologia , Piperazinas/síntese química , Piperazinas/farmacologia , Receptores de Dopamina D2/agonistas , Relação Estrutura-Atividade
9.
J Med Chem ; 40(26): 4235-56, 1997 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-9435894

RESUMO

A series of 2-(aminomethyl)chromans (2-AMCs) was synthesized and evaluated for their affinity and selectivity for both the high- and low-affinity agonist states (D2High and D2Low, respectively) of the dopamine (DA) D2 receptor. The 7-hydroxy-2-(aminomethyl)chroman moiety was observed to be the primary D2 agonist pharmacophore. The 2-methylchroman moiety was discovered to be an entirely novel scaffold which could be used to access the D2 agonist pharmacophore. Attaching various simple alkyl and arylalkyl side chains to the 7-hydroxy 2-AMC nucleus had significant effects on selectivity for the D2High receptor vs the 5HT1A and alpha 1 receptors. A novel DA partial agonist, (R)-(-)-2-(benzylamino)methyl)chroman-7-ol [R-(-)-35c], was identified as having the highest affinity and best selectivity for the D2High receptor vs the alpha 1 and 5HT1A receptors. Several regions of the 2-AMC nucleus were modified and recognized as potential sites to modulate the level of intrinsic activity. The global minimum conformer of the 7-hydroxy-2-AMC moiety was identified as fulfilling the McDermed model D2 agonist pharmacophoric criteria and was proposed as the D2 receptor-bound conformation. Structure-activity relationships gained from these studies have aided in the synthesis of D2 partial agonists of varying intrinsic activity levels. These agents should be of therapeutic value in treating disorders resulting from hypo- and hyperdopaminergic activity, without the side effects associated with complete D2 agonism or antagonism.


Assuntos
Cromanos/síntese química , Dopaminérgicos/síntese química , Receptores de Dopamina D2/agonistas , Animais , Células CHO , Cromanos/química , Cromanos/farmacologia , Cricetinae , Dopaminérgicos/química , Dopaminérgicos/metabolismo , Dopaminérgicos/farmacologia , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Camundongos , Camundongos Endogâmicos , Modelos Moleculares , Estrutura Molecular , Atividade Motora/efeitos dos fármacos , Ligação Proteica , Ratos , Ratos Sprague-Dawley , Receptores de Serotonina/metabolismo , Estereoisomerismo , Relação Estrutura-Atividade
10.
J Med Chem ; 31(7): 1382-92, 1988 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-2898533

RESUMO

A series of polycyclic aryl- and heteroarylpiperazinyl imides were prepared and tested in various receptor-binding and behavioral tests. Parameters measured included in vitro inhibition of D2 and 5-HT1A receptor binding, inhibition of apomorphine (APO) induced stereotyped and climbing behavior, and activity in blocking conditioned avoidance responding (CAR). Several compounds demonstrated moderate to high affinity for the 5-HT1A receptor binding site; compounds 27 and 36 containing the serotonin mimetic (o-methoxyphenyl)piperazinyl moiety and compounds 42 and 50 containing the 2-pyrimidinylpiperazinyl moiety displayed the highest affinity, being equal to that of the 5-HT1A agonist 8-OH-DPAT (Ki = 1-1.3 nM). In addition to affinity at 5-HT1A binding sites, many compounds were active in blocking CAR. Compound 34, 2-[4-[4-(2-pyrimidinyl)-1-piperazinyl]butyl]hexahydro-4,7-etheno-1H- cyclobut[f]isoindole-1,3(2H)-dione, demonstrated 3 times the activity of buspirone, blocking CAR in rats with an AB50 of 13 mg/kg. It also displayed high affinity for the 5-HT1A receptor (Ki = 16 nM), which is at least 20 times higher than its affinity for D2 (Ki = 345 nM) and 5-HT2 (Ki = 458 nM) receptors. Compound 34 was selected for further preclinical and pharmacokinetic evaluations for possible development as an anxiolytic agent. Structure-activity relationships within this series are discussed.


Assuntos
Ansiolíticos , Imidas/síntese química , Piperazinas/síntese química , Receptores de Serotonina/metabolismo , Animais , Apomorfina/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Comportamento Animal/efeitos dos fármacos , Encéfalo/metabolismo , Fenômenos Químicos , Química , Imidas/metabolismo , Imidas/farmacologia , Masculino , Piperazinas/metabolismo , Piperazinas/farmacologia , Ratos , Ratos Endogâmicos , Receptores Dopaminérgicos/metabolismo , Receptores de Dopamina D2 , Comportamento Estereotipado/efeitos dos fármacos , Relação Estrutura-Atividade
11.
J Med Chem ; 30(10): 1818-23, 1987 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-2888898

RESUMO

Several novel substituted gamma-carbolines were synthesized and examined in a series of in vitro and in vivo pharmacological tests to determine potential antipsychotic activity. Most compounds were orally active in blocking the conditioned avoidance response (CAR) in rats but did not antagonize apomorphine-induced stereotyped behavior. Compound 17 (Wy-47,384), a gamma-carboline with a 3-(3-pyridinyl)propyl side chain, was selected for development as an atypical antipsychotic agent because of its potent and selective profile in preclinical psychopharmacological tests. It blocked CAR in rats with an AB50 of 14 mg/kg po, showed weak affinity for the D2 receptor site (Ki = 104 nM), and showed differential potency in antagonizing apomorphine-induced stereotyped behavior (ED50 = 11 mg/kg ip) and climbing behavior (ED50 = 4 mg/kg ip). Such activities are suggestive of antipsychotic efficacy combined with a low potential for extrapyramidal side effect (EPS) liability.


Assuntos
Antipsicóticos/farmacologia , Carbolinas/farmacologia , Animais , Antipsicóticos/síntese química , Apomorfina/farmacologia , Aprendizagem da Esquiva/efeitos dos fármacos , Carbolinas/síntese química , Masculino , Camundongos , Ratos , Receptores Dopaminérgicos/metabolismo , Espiperona/metabolismo , Comportamento Estereotipado/efeitos dos fármacos , Relação Estrutura-Atividade
12.
Brain Res Bull ; 19(4): 465-71, 1987 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-2825928

RESUMO

Amperozide (AB Ferrosan, FG 5606), a new antiaggressive agent which exhibits a diverse preclinical profile of in vivo and in vitro activities, was examined to determine its acute effects on noradrenergic neurons of the locus coeruleus. The firing rates of all locus coeruleus neurons tested were increased by IV administration of amperozide. The amperozide-induced increase in locus coeruleus firing rate was similar in magnitude to that of an alpha-2 antagonist; however, amperozide was weaker than the alpha-2 antagonist yohimbine in reversing clonidine-induced inhibition of locus coeruleus neuronal activity and had weak affinity at the alpha-2 receptor (Ki = 3.5 microM). Biochemically, amperozide displayed the most significant in vitro affinity at serotonin-2 receptors (Ki = 26 nM) and had low affinities at all other receptors examined. These properties are discussed in the context of amperozide's activation of the locus coeruleus as a part of its hypothetical mechanism of antiaggressive action.


Assuntos
Locus Cerúleo/fisiologia , Piperazinas/administração & dosagem , Psicotrópicos/administração & dosagem , Potenciais de Ação/efeitos dos fármacos , Animais , Injeções Intravenosas , Locus Cerúleo/efeitos dos fármacos , Locus Cerúleo/metabolismo , Masculino , Inibição Neural/efeitos dos fármacos , Norepinefrina/metabolismo , Piperazinas/metabolismo , Piperazinas/farmacologia , Psicotrópicos/metabolismo , Psicotrópicos/farmacologia , Ratos , Ratos Endogâmicos , Receptores de Neurotransmissores/efeitos dos fármacos , Receptores de Neurotransmissores/metabolismo , Serotonina/metabolismo
13.
J Neurochem ; 46(1): 191-7, 1986 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-2866233

RESUMO

In addition to antidepressant drugs, some neuroleptic (NL) drugs reduce serotonin2 (5-HT2) receptor binding sites after chronic administration. The present study was undertaken to characterize further this property of NL drugs. Scatchard analysis of [3H]spiperone binding in rat cerebral cortex revealed that 21-day treatment with chlorpromazine (CPZ), cis-flupenthixol, and thioridazine reduced 5-HT2 radioligand binding density by 60, 27, and 18%, respectively. The more selective dopamine-D2 antagonists haloperidol and sulpiride were totally ineffective in this regard. No reduction in 5-HT2 ligand binding sites occurred after 1 day of treatment with CPZ but 3-days of treatment was effective and this reduction persisted, although diminished, for at least 72 h after the last injection. cis-Flupenthixol and d-butaclamol were also effective after 3 days of treatment but trans-flupenthixol and l-butaclamol were not, indicating stereo-specificity of the response mechanism. Female rats showed the same response to CPZ as did male rats. Central 5,7-dihydroxytryptamine-induced lesions of 5-HT neurons demonstrated that intact 5-HT neurons were not required for the reduction of 5-HT2 receptor ligand binding by CPZ. Since CPZ has high affinity for many receptors, including alpha 1, histamine1, and muscarinic receptors, the role of these effects in producing 5-HT2 receptor down-regulation was considered by studying the effects of prazosin, atropine, and pyrilamine administration on 5-HT2 radioligand binding. Results indicate that no one of these actions appears to account for the down-regulation of 5-HT2 receptors by CPZ. Several of these effects, in combination, or some unique mechanism, may be involved.


Assuntos
Antipsicóticos/farmacologia , Córtex Cerebral/efeitos dos fármacos , Receptores de Serotonina/efeitos dos fármacos , 5,7-Di-Hidroxitriptamina/farmacologia , Animais , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiologia , Clorpromazina/farmacologia , Clozapina/farmacologia , Feminino , Haloperidol/farmacologia , Imipramina/farmacologia , Ketanserina , Loxapina/farmacologia , Masculino , Piperidinas/farmacologia , Ratos , Ratos Endogâmicos , Receptores de Serotonina/metabolismo , Serotonina/metabolismo , Espiperona/metabolismo , Sulpirida/farmacologia
14.
J Med Chem ; 27(5): 654-9, 1984 May.
Artigo em Inglês | MEDLINE | ID: mdl-6325692

RESUMO

A series of phosphorus compounds, designed as analogues of gamma-aminobutyric acid (GABA) in that they possess a P = O moiety separated by three atoms from an amino or acetamido group, was synthesized and tested by using in vitro GABAA and GABAB receptor binding, GABA uptake assays, and was examined for anticonvulsant activity. Weak GABAB receptor affinity was noted for one agent, whereas six compounds displayed moderate to high potencies as inhibitors of electroshock- and pentylenetetrazol-induced seizures. The best anticonvulsant effect was found with the (m-aminophenyl) phosphinic acid compounds, with members of this class selected for further study.


Assuntos
Anticonvulsivantes/síntese química , Compostos Organofosforados/síntese química , Ácido gama-Aminobutírico/análogos & derivados , Animais , Bioensaio , Encéfalo/metabolismo , Indicadores e Reagentes , Espectroscopia de Ressonância Magnética , Camundongos , Compostos Organofosforados/farmacologia , Compostos Organofosforados/uso terapêutico , Ratos , Receptores de Superfície Celular/efeitos dos fármacos , Receptores de Superfície Celular/metabolismo , Receptores de GABA-A , Convulsões/tratamento farmacológico , Espectrofotometria Infravermelho , Relação Estrutura-Atividade , Sinaptossomos/efeitos dos fármacos , Sinaptossomos/metabolismo , Ácido gama-Aminobutírico/síntese química , Ácido gama-Aminobutírico/metabolismo , Ácido gama-Aminobutírico/farmacologia , Ácido gama-Aminobutírico/uso terapêutico
16.
Neurosci Lett ; 40(2): 99-103, 1983 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-6633977

RESUMO

Cholinergic muscarinic receptor binding was analyzed in the rat brain anterior cingulate cortex following lesions of the mediodorsal or anterior thalamic nuclei, or the diagonal band of Broca. A significant change in receptor binding was noted only after lesions of the mediodorsal projection, suggesting that cholinergic muscarinic receptors are located on these terminals. These findings suggest that the projection from the diagonal band of Broca which is cholinergic may act as a modulator of the mediodorsal thalamic projection.


Assuntos
Fibras Colinérgicas/metabolismo , Giro do Cíngulo/metabolismo , Receptores Muscarínicos/metabolismo , Núcleos Talâmicos/metabolismo , Animais , Hipocampo/metabolismo , Cinética , Masculino , Vias Neurais/metabolismo , Quinuclidinil Benzilato/metabolismo , Ratos , Ratos Endogâmicos , Núcleos Septais/metabolismo
18.
Biochem Pharmacol ; 31(5): 825-30, 1982 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-7082351

RESUMO

The selectivity of benserazide and phenelzine toward inhibition of benzylamine oxidase (BzAO) and monoamine oxidases (MAO-A and MAO-B) was studied in homogenates of rat skull and lung. In addition, the kinetic interaction and reversibility of BzAO inhibition were assessed. Both drugs inhibited BzAO but only phenelzine inhibited MAO, whether tested in vitro or in vivo. Neither compound acted as an irreversible inhibitor of BzAO. Benserazide was found to be a noncompetitive inhibitor. Phenelzine acted as a substrate for BzAO followed by product-induced noncompetitive inhibition which was labile at 37 degrees but not at 4 degrees. A reversible component in phenelzine-induced inhibition of MAO-A and -B is also suggested from in vivo studies.


Assuntos
Benserazida/farmacologia , Benzilamina Oxidase/antagonistas & inibidores , Hidrazinas/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Fenelzina/farmacologia , Animais , Cinética , Masculino , Monoaminoxidase , Fenelzina/metabolismo , Ratos , Ratos Endogâmicos
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...