Abstract

Pomaglumetad methionil (LY2140023) is a mGlu_2/3 receptor agonist prodrug reported in 2007 to possess antipsychotic efficacy based on results of a phase 2 trial conducted entirely in Russia using in-patients with schizophrenia. Since that time, pomaglumetad methionil failed to demonstrate antipsychotic efficacy compared to placebo in three phase 2 or phase 3 trials, despite risperidone separating from placebo in one phase 3 trial. While there was some evidence of an antipsychotic effect in these studies on an a priori specified genetically-defined subpopulation based on single nucleotide polymorphisms of the 5-hydroxytryptamine_2A receptor gene (HTR2A) , these effects were modest when compared to very limited effects in the overall population of schizophrenic patients responding to SOC second generation antipsychotic drugs. Post-hoc analyses also suggested antipsychotic efficacy for pomaglumetad methionil in subjects with a disease duration equal/less than 3 years or subjects previously treated with antipsychotic drugs predominantly acting at dopamine D₂ receptors compared to 5-HT_2A receptors. Orthogonal to these results with the mGlu_2/3 receptor agonist prodrug, a 5-HT_2A receptor inverse agonist pimavanserin demonstrated antipsychotic efficacy in subjects with Parkinson’s disease (PD) psychosis despite limited and at best modest evidence of antipsychotic efficacy for a number of selective 5-HT_2A receptor antagonists in subjects with schizophrenia. Based on the precedent for pimavanserin in PD psychosis, the known overlapping preclinical profile of mGlu_2/3 receptor agonists and 5-HT_2A receptor antagonists/inverse agonists and the neurobiology of other psychosis associated with neurodegenerative illness, there remains open a hypothesis that mGlu_2/3 receptor agonists may exert clinically significant antipsychotic effects in PD psychosis, dementia with Lewy Bodies, and Alzheimer’s disease psychosis.

Keywords: Pomaglumetad methionil, LY2140023, LY404039, schizophrenia, mGlu_2/3 receptor agonists, 5-HT2A receptors, mGlu₂ receptors, Parkinson’s disease psychosis.