Isoindolinone derivatives as metabotropic glutamate receptor 1 antagonists as a potential treatment for psychotic disorders One of the major excitatory neurotransmitters in the central nervous system is glutamate. This neurotransmitter acts on ionotropic glutamate receptors, including NMDA and non-NMDA receptors and on G-protein-coupled metabotropic glutamate receptors (mGluRs). There are eight subtypes (three subclasses) of mGluRs based on sequence homology, coupling mechanisms to G-protein and pharmacological properties. mGluRs as a class are considered to be drug targets for modulating glutamate transmission and so have potential relevance in the treatment of neurological and psychiatric diseases, including epilepsy, Parkinson's disease, cognitive disorders, anxiety and schizophrenia [1,2]. Previously, it has been shown [3] that a potent and selective mGluRI allosteric antagonist (i) inhibited psychostimulant methamphetamine (MAP)-induced behavioural alterations such as hyperlocomotion. These results suggest that blockage of mGluRI mimics some effects of antipsychotics and so mGluRI antagonists could have the potential for the treatment of psychotic disorders. Compound (i) was not progressed into clinical trials because of unacceptable DMPK properties.
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