Development of novel and selective glutamate receptor modulators for the treatment of cognitive impairment in schizophrenia

Cognitive impairment in schizophrenia (CIAS) is a current unmet clinical need, with no licensed pharmacotherapy. CIAS along with negative symptoms greatly impairs quality of life and presents a large burden for the economy, carers and patients. The aim of this project is to develop new pharmacotherapy for this unmet clinical need. Disruption of glutamatergic signalling linked to NMDA receptor hypofunction has been associated with CIAS and other symptoms. Endogenous glutamate activates mGlu5 receptors (mGluR5) expressed within key circuits in brain regions involved in the pathophysiology of CIAS e.g. hippocampus and prefrontal cortex (PFC). mGlu5Rs are known to induce PI-3K/p-AKT and ERK1/2/MAPK signalling pathways, regulating synaptic plasticity (Sengmany and Gregory, 2016 Br J Pharmacol. 173(20): 3001-3017). Preclinical studies have underlined the potential of mGluR5 positive allosteric modulators (PAMs) to improve cognitive symptoms of this devastating illness. However most compounds lack selectivity and therefore have adverse effects. We intend to take a multidisciplinary approach to develop mGlu5 PAMs with enhanced specificity, so reducing adverse effects and improving efficacy. Our long-term aim is construction of a chemical library of compounds with brain area/ cell specific mGlu5 signalling profiles and consequently identification of better therapeutic compounds. To achieve this aim, we will first evaluate two known mGluR5 PAMs with a differing chemical structure; VU0409551 and VU360172 see figure below. We will compare their efficacy to restore cognitive function (and aspects of negative symptoms) in our carefully validated animal model of CIAS, sub-chronic phencyclidine (PCP) treatment in rats (see Cadinu et al. 2017 for our recent review). Seven domains of cognition are known to be impaired in schizophrenia, we will explore effects in behavioural tests for at least 5 of these domains using our battery of tests (see b-neuro.com for full details). To understand the neurobiological mechanisms underlying behavioural effects and identify pathways recruited, we will investigate effects of both compounds on mGlu5 signalling in PFC and hippocampus in post-mortem brain tissue using western blotting, immunohistochemistry and qPCR. We also aim to test efficacy in our maternal immune activation (mIA) developmental model for schizophrenia (see Murray et al. 2018). These two models represent distinct patient phenotypes. This work will be conducted at the University of Manchester, UoM. The project will also involve testing novel compounds in several in vitro assays such as electrophysiology combined with calcium imaging providing unique experience in medicinal chemistry (molecular and chemical neurobiology) at the University of Lincoln.