Molecular insights into orphan G protein-coupled receptors relevant to
schizophrenia
Abstract
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.