mGluRs & schizophrenia
Glutamate in Schizophrenia
The involvement of metabotropic glutamate receptor 2 (mGluR2) and mGluR5 in schizophrenia is expected given the glutamate hypothesis of schizophrenia, which is supported by data from multiple sources. Importantly, the effects of positive allosteric modulators of mGluR2 and mGluR5 are independent of dopamine receptors, indicating the potential for mGluR modulators to offer efficacy while avoiding the side effects associated with dopaminergic therapeutics.
mGluR2 activation (ADX71149)
There is clinical proof of concept, showing that mGluR2 activation has efficacy in schizophrenia and anxiety. A Phase II clinical study published in Nature Medicine showed that activation of mGluR2 improved symptoms of schizophrenia with efficacy similar to that of one of the leading marketed drugs. Importantly, in the Phase II study the product did not cause weight gain or extrapyramidal symptoms, which are side effects that can be associated with the use of the leading marketed drugs.
Our partner Janssen Pharmaceuticals, Inc. (JPI), formerly Ortho-McNeil-Janssen Pharmaceuticals, Inc, initiated during the first half of 2011 Phase IIa testing of ADX71149 in schizophrenia.
mGluR5 activation
The glutamate hypothesis of schizophrenia posits that the function of the N-methyl-D-Aspartate (NMDA) receptor is compromised in this disease. NMDA receptors are a major subtype of glutamate receptors, whose function is considered critical for the proper expression of complex behaviors, such as associative learning, working memory, behavioral flexibility, and attention, many of which are impaired in schizophrenia. NMDA receptors also play an essential role in the development of neural pathways, including during adolescence, making them a critical component of developmental processes whose malfunction may lead to schizophrenia.
Furthermore, there is evidence showing that mGluR5 can change the way NMDA receptors respond to glutamate. Researchers have published data showing that mGluR5 positive allosteric modulation reversed schizophrenialike brain activity induced in animals by NMDA receptor antagonists. In humans NMDA receptor antagonists are known to impair brain activity associated with cognitive functions including learning, attention and memory, plus other symptoms seen in schizophrenia. Additionally, research has shown that in preclinical models of psychosis and cognitive dysfunction in schizophrenia, treatment with an mGluR5 positive allosteric modulator (PAM) reversed signs of both psychosis and cognitive dysfunction. It is therefore possible that an mGluR5 PAM could reverse both the effects of excess dopamine and NMDA receptor hypofunction. In other words, in humans, an mGluR5 PAM might reverse cognitive deficits and prevent psychosis.