Mifepristone (RU-486) 91

HT-0712/IPL-455903 92 mGlu5 receptor The first, potent, selective, and structurally novel mGlu5 receptor antagonists identified were SIB-1757 (85) and SIB 1893, which led to the noncompetitive antagonists MPEP (86) and MTEP (87).62 mGlu1/5 receptors are involved in long-term potentiation (LTP), chronic depression, and memory formation.66 mGlu2/3 The mGlu2/3 agonists LY-354740 (88) and LY-379268 (89) are active in animal models of anxiety65 acting as functional 5HT2A antagonists with therapeutic implications in the treatment of mood disorders.67-69 GABAb receptor antagonist

Dysfunction of GABAergic systems are implicated in the pathophysiology of anxiety and depression. Recent evidence points to a role of GABAb receptors in anxiety and depression. Metabotropic GABAb receptors predominantly function as heterodimers of GABAB1 and GABAB2 subunits, but GABAB1 can also form functional receptors in the absence of GABAB2. Mice lacking the GABAB1 subunit have altered behavioral responses in tests for anxiety and depression. Both GABAB1- and GABAB2-deficient mice were found to be more anxious than wild type in the light-dark box paradigm.70 In contrast, these mice exhibited an antidepressant-like behavior in the FST. Taken together, these data suggest that heterodimeric GABAB12 receptors are required for the normal regulation of emotional behavior and offer a novel approach for the treatment of mood disorders.70 GABAB receptor antagonists in preclinical and clinical development for depression and cognitive disorders include AVE 1876 and SGS742 (90).

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