Glutamate is the major excitatory neurotransmitter in the central nervous system (CNS), and an imbalance in glutamatergic neurotransmission is believed to be linked to various neurological and psychiatric diseases. Metabotropic glutamate receptor 2 (mGluR2) belongs to the group II mGlu receptors that are widely expressed in the forebrain and localized presynaptically in the neurons, serving inhibitory regulation of related neurotransmission. Compounds that activate the group II mGlu receptors may offer anxiolytic and/or antipsychotic effects. Especially, it is expected that, unlike orthosteric agonists, positive allosteric modulators (PAMs) would offer higher selectivity to mGluR2 in the mGluR family as well as the potential to avoid receptor desensitization. In addition, structural diversity and physicochemical properties suitable for passive brain penetration would likely be attained for PAMs, which is generally not easy for orthosteric agonists of mGluRs. While several structural classes of mGluR2 PAMs have been reported with this background, we identified dihydropyrrolopyrazinone derivatives as new chemotypes of mGluR2 PAMs with highly potent activity and wide substituent admissibility. The further lead optimization study led to discovery of novel mGluR2 PAM (1 ), which showed oral antipsychotic effects in rats. Herein, we will discuss the design, synthesis, structure-activity relationship (SAR), pharmacokinetic (PK) properties and biological activity of our novel mGluR2 PAMs.

Discovery of dihydropyrrolopyrazinone derivatives as metabotropic glutamate receptor 2 (mGluR2) positive allosteric modulators (PAMs)

247th National Meeting (2014)

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