Ly2140023 Monohydrate: An Agonist at the Mglu2/3 Receptor for the Treatment of Schizophrenia

Validation and pharmacological characterisation of MK-801-induced locomotor hyperactivity in BALB/C mice as an assay for detection of novel antipsychotics

“…In a recent clinical trial, an mGluR2/3 agonist LY2140023 failed to improve clinical signs in patients with schizophrenia (Kinon 2009), the results questioning predictive validity of preclinical models in the detection of antipsychotic efficacy of mGluR2/3 agonists. However, the results of the study were considered to be inconclusive due to the robust response seen in placebo-treated patients and the similarity between placebo-and olanzapine-treated groups (Kinon 2009).…”

“…However, the results of the study were considered to be inconclusive due to the robust response seen in placebo-treated patients and the similarity between placebo-and olanzapine-treated groups (Kinon 2009). Thus, additional clinical data are needed in order to fully understand predictive validity of the present model in detection of antipsychotic efficacy of mGluR2/3 agonists.…”

Interaction of mGlu2/3 agonism with clozapine and lurasidone to restore novel object recognition in subchronic phencyclidine-treated rats

“…The main evidence for the deficit in glutamatergic function in schizophrenia is that noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonists, e.g., phencyclidine (PCP) and ketamine, induce schizophrenia-like cognitive impairments in healthy subjects (Javitt and Zukin 1991;Krystal et al 1999), but the hypothesis is also supported by post-mortem and genetic studies (Gunduz-Bruce 2009). There is, however, conflicting evidence about the effects of acute and chronic ketamine on declarative memory in patients with schizophrenia and normal volunteers (LaPorte et al 1996;Morgan et al 2009;Stefanovic et al 2009).…”

“…A recent phase IIA clinical trial showed that LY2140023, a prodrug that is converted into the mGlu 2/3 agonist LY404039, improved positive and negative symptoms in patients with schizophrenia (Patil et al 2007). A second phase II study with LY2140023 failed to show clinical improvement in schizophrenic patients, but it was a failed, and, therefore, inconclusive study since the positive control, olanzapine, also did not differentiate from placebo (Kinon 2009). …”

Effects of a novel mGlu2/3 receptor agonist prodrug, LY2140023 monohydrate, on central monoamine turnover as determined in human and rat cerebrospinal fluid

“…A second study of LY2140023 monohydrate in schizophrenia where both LY2140023 monohydrate and olanzapine failed to show a significant effect was considered inconclusive due to an unexpectedly large placebo response (Kinon et al 2010). …”