ORPHAN GPCRS – A NEW FRONTIER IN SCHIZOPHRENIA DRUG DISCOVERY

Abstract Background Schizophrenia manifests as a broad and diverse symptomatology that creates a heterogenous patient population that responds to standard of care medicines to varying extents. The three characterised symptom domains; positive, negative and cognitive, represent, but are not limited to: hallucinations and delusions, negative affect, and impairments in learning and memory, respectively. Frontline drugs only effectively address the positive symptoms in ~70% of patients, yet it is the cognitive impairments associated with schizophrenia (CIAS) that pose the greatest hurdle to improve societal integration and quality of life. These issues culminate in a critical unmet medical need. There have been a number of clinical candidates and mechanisms that have sought to address CIAS, and all have failed. These failures point to two probable influences: 1. insufficient insight into the mechanisms capable of driving a change in disease symptoms; 2. the lack of stringent preclinical models and assays that derive endpoints similar to those tested in patients. Whilst schizophrenia standard of care medicines and investigational agents engage a number of G protein-coupled receptors (GPCRs), there remains an array of CNS-enriched orphan GPCRs that represent new opportunities as drug targets (Lu et al., 2023). Objective Our approach employs a holistic workflow to target validation and drug discovery through applying techniques that accelerates the process whilst increasing fidelity. We have applied structure- enabled drug design, disease-relevant pharmacology and advanced rodent models to multiple orphan GPCRs to create a global understanding of the target ranging from ligand-receptor interactions to in- depth behavioural insights. Method We used cryogenic electron microscopy to generate molecular models of our target orphan GPCRs in complex with their cognate G proteins to gain molecular insights into ligand binding and G protein coupling – facilitating structure-based drug design. We applied multi-endpoint pharmacology in recombinant and primary native cells to provide granularity to ligand-mediated signalling sequalae. Finally, we overlayed these findings with a comprehensive behavioural and cognitive battery (including rodent cognition touchscreens) to provide a correlation between our ligand-receptor mechanisms and psychosis- and cognition-relevant in vivo behavioural outcomes. Results Application of our technical workflow has provided molecular insights to accelerate ligand optimisation and deliver ligands with distinct, signal-biased pharmacological profiles. These ligands demonstrated antipsychotic activity (reversal of hyperlocomotion) and distinct cognition-enhancing profiles in mice, across working memory and attention tasks. Conclusions Development of this unique workflow has allowed the deconvolving of mechanisms of ligand-receptor interactions and signalling that accelerated development of ligands that target orphan GPCRs and display antipsychotic and pro-cognitive effects in mice. References Lu Y. 2023. Molecular insights into orphan G protein-coupled receptors relevant to schizophrenia. Br J Pharmacol. doi: 10.1111/bph.16221