Pomaglumetad (LY-404,039) is an amino acid analog drug that acts as a highly selective agonist for the metabotropic glutamate receptor group II subtypes mGluR2 and mGluR3. Pharmacological research has focused on its potential antipsychotic and anxiolytic effects. Pomaglumetad is intended as a treatment for schizophrenia and other psychotic and anxiety disorders by modulating glutamatergic activity and reducing presynaptic release of glutamate at synapses in limbic and forebrain areas relevant to these disorders. Human studies investigating therapeutic use of pomaglumetad have focused on the prodrug LY-2140023, a methionine amide of pomaglumetad (also called pomaglumetad methionil) since pomaglumetad exhibits low oral absorption and bioavailability in humans.
Early human trials using this prodrug form of pomaglumetad gave encouraging results. However, pharmaceutical company Eli Lilly terminated further development of the compound in 2012 after it failed in phase III clinical trials. In September 2013, the results of a randomized, placebo-controlled clinical trial investigating the impact of adjunctive LY-2140023 on prominent negative symptoms in schizophrenia was published and failed to demonstrate any benefit.
In 2015, Denovo Biopharma exclusively licensed LY-2140023 (the prodrug) for further development, having identified "a meaningful subset of patients who showed significantly improved outcomes".
Pharmacology
Mechanism of action and pharmacodynamics
Clinical development of pomaglumetad resulted from efforts to discover potent and selective mGluR agonists for the treatment of psychiatric disorders. Pomaglumetad is highly selective for group II metabotropic glutamate receptors mGluR2 and mGluR3. These receptors reduce the activity of postsynaptic potentials in the cortex and act by inhibiting the release of glutamate and GABA. pomaglumetad has been shown to act as a potent full agonist at group II mGluRs as demonstrated by its ability to inhibit cyclic adenosine monophosphate, cAMP, formation as a result of stimulation by forskolin. Pomaglumetad has been shown to modulate glutamatergic activity in the limbic and forebrain areas, where group II mGlu receptors are most densely localized.
The specific binding of pomaglumetad to human cloned mGlu receptors has been found to be highest for mGluR2 (K = 149 ± 11 nM) and relatively high for mGluR3 (K = 92 ± 14 nM). Research suggests that it does not have any appreciable affinity for other metabotropic glutamate receptors, ionotropic NMDA receptors, or kainate receptors, nor does it appear to have any affinity for adrenergic, benzodiazepine/GABAergic, histaminergic or muscarinic receptors. The functional activity of pomaglumetad on mGluR receptors has been further demonstrated by investigating the drug's ability to suppress electrically stimulated excitatory postsynaptic potentials, or EPSPs. Pomaglumetad has been shown to attenuate cortically evoked EPSPs in rat striatal spiny neurons in a concentration-dependent manner, mediated by activation of mGluR2 and mGluR3 receptors. This suppressive effect of pomaglumetad on stimulated EPSPs is reversed by the use of mGluR2/3 antagonists, such as LY341495.
Pomaglumetad possesses partial agonist actions at D2 receptors and inhibits the binding of the D2-specific antagonist [3H]domperidone to human cloned D2 receptors. It increases the release of dopamine as well as its metabolites DOPAC and HVA in the prefrontal cortex in a manner similar to the atypical antipsychotic clozapine. Pomaglumetad also appears to have some effects on serotonin. It has been shown that pomaglumetad increases serotonin turnover, increasing the ratio of 5-HIAA to 5-HT, and suppresses serotonin-induced glutamate release in the prefrontal cortex.
There is disagreement in the literature as to the possible agonistic action that pomaglumetad has on dopamine receptors. Attempts by Eli Lilly and AstraZeneca to replicate findings showing potent partial agonist action of mGluR2/3 agonists at D2 receptors were unsuccessful.
Novelty
Based on the glutamate hypothesis of schizophrenia, glutamate receptor agonists have been suggested as an effective treatment for psychotic patients. Pomaglumetad was one of the first drugs to be suggested as effective in treating psychosis without any apparent interference in dopaminergic function. Existing antipsychotic medications primarily treat schizophrenia by acting as antagonists at D2 receptors, while pomaglumetad has very low affinity for biogenic amine receptors.