Targeting of Metabotropic Glutamate Receptors for the Development ofNovel Antidepressants

摘要

Since discovering that ketamine has robust antidepressant effects, theglutamatergic system has been proposed as an attractive target for thedevelopment of novel antidepressants. Among the glutamatergic system,metabotropic glutamate (mGlu) receptors are of interest because mGlu receptorsplay modulatory roles in glutamatergic transmission, consequently, agents actingon mGlu receptors might not exert the adverse effects associated with ketamine.mGlu receptors have eight subtypes that are classified into three groups, andthe roles of each mGlu receptor subtype in depression are being investigated. Todate, the potential use of mGlu5 receptor antagonists and mGlu2/3 receptorantagonists as antidepressants has been actively investigated, and themechanisms underlying these antidepressant effects are being delineated.Although the outcomes of clinical trials using an mGlu5 receptor negativeallosteric modulator and an mGlu2/3 receptor negative allosteric modulator havenot been encouraging, these trials have been inconclusive, and additional trialsusing other compounds with more appropriate profiles are needed. In contrast,the roles of group III mGlu receptors have not yet been fully elucidated becauseof a lack of suitable pharmacological tools. Nonetheless, investigations of theuse of mGlu4 and mGlu7 receptors as drug targets for the development ofantidepressants have been ongoing, and some interesting evidence has beenobtained.