Substance use disorder (SUD) is a chronic condition with maintained abuse of a substance leading to physiological and psychological alterations and often changes in cognitive and social behaviours. Current therapies mainly consist of psychotherapy coupled with medication; however, alarmingly high relapse rates reveal the shortcomings of the current standard of care. The signalling and expression profile, and neurological function of the serotonin 2C receptor (5-HT2C receptor) make it an ideal candidate of interest for the treatment of SUD. This is further corroborated by pre-clinical and clinical evidence of therapeutically relevant compounds acting at the 5-HT2C receptor. Notwithstanding, drug binding at closely related serotonin receptor subtypes has impeded drug development. More recently, psychedelics, which broadly act at 5-HT2 receptors, have indicated promising potential for the treatment of SUD, implicating in part, the 5-HT2C receptor. The modern psychedelic movement has rekindled therapeutic interest in the 5-HT2C receptor, resulting in an influx of new studies, especially structural analyses. This review delves into the structural, molecular and cellular mechanisms governing the 5-HT2C receptor function, in the context of SUD. This provides the basis of the preclinical and clinical evidence for their role in SUD and highlights the potential for future exploration.

Schizophrenia remains a sizable socioeconomic burden that continues to be treated with therapeutics based on 70-year old science. All currently approved therapeutics primarily target the dopamine D2 receptor to achieve their efficacy. Whilst dopaminergic dysregulation is a key feature in this disorder, the targeting of dopaminergic machinery has yielded limited efficacy and an appreciable side effect burden. Over the recent decades, numerous drugs that engage non-dopaminergic GPCRs have yielded a promise of efficacy without the deleterious side effect profile, yet none have successfully completed clinical studies and progressed to the market. More recently, there has been increased attention around non-dopaminergic GPCR-targeting drugs, notably KarXT, which demonstrated efficacy in some schizophrenia symptom domains. This provides renewed hope that effective schizophrenia may lay outside of the dopaminergic space. Despite the potential for muscarinic receptor- (and other well-characterised GPCR families) targeting drugs to treat schizophrenia, they are often plagued with complications such as lack of receptor subtype selectivity and peripheral on-target side-effects. Orphan GPCR studies have opened a new avenue of exploration with many demonstrating schizophrenia-relevant mechanisms and a favourable expression profile, thus offering potential for novel drug development. This review discusses centrally-expressed orphan G protein-coupled receptors: GPR3, GPR6, GPR12, GPR52, GPR85, GPR88 and GPR139 and their relationship to schizophrenia. We review their expression, signalling mechanisms and cellular function, in conjunction with small molecule development and structural insights. We seek to provide a snapshot of the growing evidence and development potential of new classes of schizophrenia therapeutics.