RESUMO
Parkinson's disease (PD) patients suffer not only from the primary motor symptoms of the disease but also from a range of non-motor symptoms (NMS) that cause disability and low quality of life. Excessive glutamate activity in the basal ganglia resulting from degeneration of the nigrostriatal dopamine pathway has been implicated in the motor symptoms, NMS and dyskinesias in PD patients. In this study, we investigated the effects of a selective mGlu5 negative allosteric modulator (NAM), dipraglurant, in a rodent motor symptoms model of PD, but also in models of anxiety, depression and obsessive-compulsive disorder, all of which are among the most prevalent NMS symptoms. Dipraglurant is rapidly absorbed after oral administration, readily crosses the blood-brain barrier, and exhibits a high correlation between plasma concentration and efficacy in behavioral models. In vivo, dipraglurant dose-dependently reduced haloperidol-induced catalepsy, increased punished licks in the Vogel conflict-drinking model, decreased immobility time in the forced swim test, decreased the number of buried marbles in the marble-burying test, but had no effect on rotarod performance or locomotor activity. These findings suggest that dipraglurant may have benefits to address some of the highly problematic comorbid non-motor symptoms of PD, in addition to its antidyskinetic effect demonstrated in PD-LID patients.
Assuntos
Doença de Parkinson , Humanos , Doença de Parkinson/tratamento farmacológico , Qualidade de Vida , Piridinas/farmacologia , Imidazóis/farmacologiaRESUMO
Glutamate is the principle excitatory neurotransmitter in the mammalian brain, and dysregulation of glutamatergic neurotransmission is implicated in the pathophysiology of several psychiatric and neurological diseases. This study utilized novel lentiviral short hairpin RNA (shRNA) vectors to target expression of the vesicular glutamate transporter 1 (VGLUT1) following injection into the dorsal hippocampus of adult mice, as partial reductions in VGLUT1 expression should attenuate glutamatergic signaling and similar reductions have been reported in schizophrenia. The VGLUT1-targeting vector attenuated tonic glutamate release in the dorsal hippocampus without affecting GABA, and selectively impaired novel object discrimination (NOD) and retention (but not acquisition) in the Morris water maze, without influencing contextual fear-motivated learning or causing any adverse locomotor or central immune effects. This pattern of cognitive impairment is consistent with the accumulating evidence for functional differentiation along the dorsoventral axis of the hippocampus, and supports the involvement of dorsal hippocampal glutamatergic neurotransmission in both spatial and nonspatial memory. Future use of this nonpharmacological VGLUT1 knockdown mouse model could improve our understanding of glutamatergic neurobiology and aid assessment of novel therapies for cognitive deficits such as those seen in schizophrenia.
Assuntos
Transtornos Cognitivos/induzido quimicamente , Transtornos Cognitivos/genética , Técnicas de Transferência de Genes , Vetores Genéticos/administração & dosagem , Hipocampo/patologia , RNA Interferente Pequeno/administração & dosagem , Proteína Vesicular 1 de Transporte de Glutamato/antagonistas & inibidores , Proteína Vesicular 1 de Transporte de Glutamato/genética , Animais , Linhagem Celular , Transtornos Cognitivos/metabolismo , Vetores Genéticos/genética , Lentivirus/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , RNA Interferente Pequeno/genética , Proteína Vesicular 1 de Transporte de Glutamato/metabolismoRESUMO
Allosteric modulators of metabotropic glutamate receptors (mGluR) subtypes 1-8 have been shown to offer a valid way to develop small molecule non aminoacid-like therapeutics that can be administered orally and that readily cross the blood-brain barrier. Allosteric modulators of glutamatergic receptors and in particular mGluR5 have emerged as a novel and highly desirable class of compounds for the treatment of central nervous system (CNS) disorders and peripheral disorders. This article provides medicinal chemistry highlights around the chemical classes of potent and highly selective mGluR5 negative allosteric modulators (NAMs) and their therapeutic potential. In addition, it describes the medicinal chemistry approach from the discovery to the clinical candidate selection of a new series of heteroaryl-butynylpyridines targeting mGluR5. The multiparametric optimization of the initial starting point which ended in the selection of potential clinical candidates combining the best pharmacophoric features is presented. The pharmacological properties are reported and support the interest of these agents for new therapeutic approaches. Furthermore, a summary of the diverse mGluR5 Positron Emission Tomography (PET) radioligands is reported.
Assuntos
Compostos Heterocíclicos/farmacologia , Piridinas/farmacologia , Receptores de Glutamato Metabotrópico/antagonistas & inibidores , Regulação Alostérica/efeitos dos fármacos , Química Farmacêutica , Desenho de Fármacos , Compostos Heterocíclicos/síntese química , Compostos Heterocíclicos/química , Tomografia por Emissão de Pósitrons , Piridinas/síntese química , Piridinas/química , Receptor de Glutamato Metabotrópico 5 , Receptores de Glutamato Metabotrópico/química , Receptores de Glutamato Metabotrópico/metabolismo , Relação Estrutura-AtividadeRESUMO
A series of 1,5-disubstituted pyridones was identified as positive allosteric modulators (PAMs) of the metabotropic glutamate receptor 2 (mGluR2) via high throughput screening (HTS). Subsequent SAR exploration led to the identification of several compounds with improved in vitro activity. Lead compound 8 was further profiled and found to attenuate the increase in PCP induced locomotor activity in mice.