RESUMO
The trace amine-associated receptor 1 (TAAR1), activated by endogenous metabolites of amino acids like the trace amines p-tyramine and ß-phenylethylamine, has proven to be an important modulator of the dopaminergic system and is considered a promising target for the treatment of neuropsychiatric disorders. To decipher the brain functions of TAAR1, a selective TAAR1 agonist, RO5166017, was engineered. RO5166017 showed high affinity and potent functional activity at mouse, rat, cynomolgus monkey, and human TAAR1 stably expressed in HEK293 cells as well as high selectivity vs. other targets. In mouse brain slices, RO5166017 inhibited the firing frequency of dopaminergic and serotonergic neurons in regions where Taar1 is expressed (i.e., the ventral tegmental area and dorsal raphe nucleus, respectively). In contrast, RO5166017 did not change the firing frequency of noradrenergic neurons in the locus coeruleus, an area devoid of Taar1 expression. Furthermore, modulation of TAAR1 activity altered the desensitization rate and agonist potency at 5-HT(1A) receptors in the dorsal raphe, suggesting that TAAR1 modulates not only dopaminergic but also serotonergic neurotransmission. In WT but not Taar1(-/-) mice, RO5166017 prevented stress-induced hyperthermia and blocked dopamine-dependent hyperlocomotion in cocaine-treated and dopamine transporter knockout mice as well as hyperactivity induced by an NMDA antagonist. These results tie TAAR1 to the control of monoamine-driven behaviors and suggest anxiolytic- and antipsychotic-like properties for agonists such as RO5166017, opening treatment opportunities for psychiatric disorders.
Assuntos
Monoaminas Biogênicas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Transmissão Sináptica/fisiologia , Animais , Benzodioxóis/farmacologia , Dopamina/metabolismo , Glutamina/metabolismo , Células HEK293 , Humanos , Transtornos Mentais , Camundongos , Fenilpropionatos/farmacologia , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/deficiênciaRESUMO
Benzoylisoindolines were discovered as a novel structural class of GlyT1 inhibitors. SAR studies and subsequent lead optimization efforts focused primarily on addressing hERG liability and on improving in vivo efficacy resulted in the identification of potent GlyT1 inhibitors displaying excellent selectivity and in vivo PD and PK profiles.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Animais , Permeabilidade da Membrana Celular , Descoberta de Drogas , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Glicina/análise , Humanos , Isoindóis/química , Isoindóis/farmacocinética , Isoindóis/farmacologia , Camundongos , Ratos , Solubilidade , Relação Estrutura-AtividadeRESUMO
RATIONALE: Neonatal ventral hippocampal lesions in rats have been shown to result in behavioral abnormalities at adulthood thought to simulate some aspects of positive and cognitive deficits classically observed in schizophrenic patients. OBJECTIVES: We investigated whether such lesions can also induce deficits in reward sensitivity that are related to the negative symptoms of psychotic disorders. METHODS: To investigate the effects of neonatal and adult lesions of the ventral hippocampus on reward-related behaviors we used the conditioned place preference (CPP) test and the saccharin consumption model. RESULTS: In contrast to adult-lesioned animals, neonatally lesioned rats exhibited a deficit in amphetamine-induced CPP and a significant reduction in saccharin preference. These deficits are unlikely due to lesion-induced motor impairments as both neonatal- and adult-lesioned rats exhibited a similar hyperlocomotor response to amphetamine. CONCLUSIONS: Taken together, these results show that neonatal ventral hippocampal lesions induce a reduction in reward-seeking behaviors in adulthood that mimic some aspects of the negative symptoms (anhedonia) in psychotic patients.
Assuntos
Modelos Animais de Doenças , Hipocampo/fisiologia , Recompensa , Esquizofrenia/fisiopatologia , Fatores Etários , Animais , Animais Recém-Nascidos , Condicionamento Psicológico/fisiologia , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/crescimento & desenvolvimento , Ácido Ibotênico/efeitos adversos , Masculino , Atividade Motora/fisiologia , Ratos , Ratos Sprague-Dawley , Esquizofrenia/induzido quimicamenteRESUMO
3-Amido-3-aryl-piperidines were discovered as a novel structural class of GlyT1 inhibitors. The structure-activity relationship, which was developed, led to the identification of highly potent compounds exhibiting excellent selectivity against the GlyT2 isoform, drug-like properties, and in vivo activity after oral administration.
RESUMO
Dysfunctional N-methyl-d-aspartate (NMDA) receptor neurotransmission has been implicated in the pathophysiology of schizophrenia. It is thought that this abnormal functioning can be corrected by increasing availability of the NMDA co-agonist glycine through inhibition of glycine transporter type 1 (GlyT1). Herein is described the pharmacologic profile of RG1678, a potent and noncompetitive glycine reuptake inhibitor. In vitro, RG1678 noncompetitively inhibited glycine uptake at human GlyT1 with a concentration exhibiting half-maximal inhibition (IC(50)) of 25 nM and competitively blocked [(3)H]ORG24598 binding sites at human GlyT1b in membranes from Chinese hamster ovary cells. In hippocampal CA1 pyramidal cells, RG1678 enhanced NMDA-dependent long-term potentiation at 100 nM but not at 300 nM. In vivo, RG1678 dose-dependently increased cerebrospinal fluid and striatal levels of glycine measured by microdialysis in rats. Additionally RG1678 attenuated hyperlocomotion induced by the psychostimulant d-amphetamine or the NMDA receptor glycine site antagonist L-687,414 in mice. RG1678 also prevented the hyper-response to d-amphetamine challenge in rats treated chronically with phencyclidine, an NMDA receptor open-channel blocker. In the latter experiment, a decrease in ex vivo striatal [(3)H]raclopride binding was also measured. These data demonstrate that RG1678 is a potent, noncompetitive glycine reuptake inhibitor that can modulate both glutamatergic and dopaminergic neurotransmission in animal experiments that model aspects of schizophrenia. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.
Assuntos
Região CA1 Hipocampal/efeitos dos fármacos , Potenciação de Longa Duração/efeitos dos fármacos , Piperazinas/farmacologia , Sulfonas/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Anfetamina/farmacologia , Animais , Células CHO , Linhagem Celular , Estimulantes do Sistema Nervoso Central/farmacologia , Cricetinae , Relação Dose-Resposta a Droga , Alucinógenos/farmacologia , Humanos , Camundongos , Atividade Motora/efeitos dos fármacos , Fenciclidina/farmacologia , Ratos , Ratos Sprague-DawleyRESUMO
Multiple lines of evidence support the notion that hypofunction of glutamatergic neurotransmission is involved in the pathophysiology of schizophrenia. Moreover, glycine and glycine modulators have beneficial effects in patients with schizophrenia, particularly when added on to existing therapy. As glycine is an obligatory co-agonist at the NR1 subunit of the NMDA receptor, blockade of glycine uptake at the glycine transporter type-1 (GlyT1) can enhance low glutamatergic tone. L-687,414 is an antagonist at the glycine modulatory site of the NMDA complex and, behaviorally, increases locomotion. A series of GlyT1 inhibitors along with other psychoactive compounds were examined for their ability to enhance or inhibit the action of L-687,414. GlyT1 inhibitors and the other compounds were examined initially for effects on [(3)H]-glycine uptake in CHO cells expressing hGlyT1b cDNA and for their ability to displace the NMDA-glycine site ligand [(3)H]-L-689,560 from isolated rat forebrain membrane preparations. The in vivo activity of these compounds was determined in mice by measuring their ability to prevent L-687,414-induced hyperlocomotion. GlyT1 inhibitors blocked [(3)H]-glycine uptake in cells expressing the human transporter; other compounds had little or no activity. None of the compounds had affinity for the glycine site of the NMDA receptor complex. Hyperlocomotion induced by L-687,414 was dose-dependently reduced by GlyT1 inhibitors and antipsychotic drugs but not by morphine, fluoxetine or a moderate dose of diazepam. Therefore, this behavioral approach can reliably detect GlyT1 inhibitors which, in turn, may have some activity in common with drugs having antipsychotic effects.
Assuntos
Antipsicóticos/farmacologia , Glicinérgicos/farmacologia , Proteínas da Membrana Plasmática de Transporte de Glicina/antagonistas & inibidores , Aminoquinolinas/antagonistas & inibidores , Aminoquinolinas/metabolismo , Aminoquinolinas/farmacologia , Animais , Sítios de Ligação/efeitos dos fármacos , Ligação Competitiva/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Linhagem Celular , Cricetinae , Cricetulus , DNA Complementar/biossíntese , DNA Complementar/genética , Relação Dose-Resposta a Droga , Antagonistas de Aminoácidos Excitatórios/metabolismo , Antagonistas de Aminoácidos Excitatórios/farmacologia , Fluoxetina/farmacologia , Glicina/metabolismo , Humanos , Masculino , Membranas/efeitos dos fármacos , Membranas/metabolismo , Camundongos , Morfina/farmacologia , Atividade Motora/efeitos dos fármacos , Inibidores da Captação de Neurotransmissores/farmacologia , Inibidores Seletivos de Recaptação de Serotonina/farmacologiaRESUMO
The GlyT1 transporter has emerged as a key novel target for the treatment of schizophrenia. Herein, we report on the optimization of the 2-alkoxy-5-methylsulfonebenzoylpiperazine class of GlyT1 inhibitors to improve hERG channel selectivity and brain penetration. This effort culminated in the discovery of compound 10a (RG1678), the first potent and selective GlyT1 inhibitor to have a beneficial effect in schizophrenic patients in a phase II clinical trial.