Schizophrenia is a disease state which describes the abnormalities of the brain such as ventricle enlargement, grey matter volume reduction as well as cortical and cerebellar atrophy1. Despite many years of investigations, no comprehensive treatments have been developed, in part due to the complex pathophysiology and inconsistent clinical features of schizophrenia. There are three types of clinical features of this disease: positive symptoms, negative symptoms, and cognitive impairment2. Current standard-of-care therapeutics address only one clinical feature of the disorder (the positive symptoms) and cause significant side effects, often leading to discontinuation of treatment3. Hence, a novel and effective treatment with fewer side effects is urgently required to treat the multifaceted nature of schizophrenia. GPR52 is an orphan G protein-coupled receptor (GPCR) with a unique localisation and signalling profile in the brain that is relevant to the pathology of schizophrenia4-6. This suggests that GPR52 could be an effective target for the treatment of the full spectrum of schizophrenia symptoms. The GPR52 agonist, 3-BTBZ, has recently been identified based on traditional cAMP-based screening. However, we have insights suggesting that 3-BTBZ-mediated GPR52 activation of substrates relating to cognition in frontal cortical neurons is dependent on the β-arrestin-2 signalling cascade7. This finding provides an opportunity to design a novel antipsychotic and pro-cognitive therapeutic treatment by enhancing the potency towards the β-arrestin-2 recruitment. This project will discuss the structure-activity relationship (SAR) exploration and optimisation of newly designed GPR52 targets towards the β-arrestin-2 biased signalling using 3-BTBZ as a template.