Development of novel potent ligands for GPR85, an orphan G protein‐coupled receptor expressed in the brain

Abstract

GPR85 is a member of the G protein-coupled receptor and is a super-conserved receptor expressed in the brain sub-family (Super Conserved Receptor Expressed in Brain; SREB) with GPR27 and GPR173. These three receptors are "orphan receptors"; however, their endogenous ligands have not been identified. SREB has garnered the interest of many scientists because it is expressed in the central nervous system and is evolutionarily conserved. In particular, brain mass is reported to be increased and learning and memory are improved in GPR85 knockout mice (Matsumoto et al. 2008). In this study, we characterized newly synthesized compounds using a GPR85-Gsα fusion protein and the [ 35 S]GTPγS binding assay and identified novel GPR85 inverse-agonists with

The role of orphan G protein-coupled receptors in pain

“…Notably, neuropeptide-receptor systems in the BLA have been shown to be critical for anxiety and mood disorders [ 130 ]. Finally, GPR85 has been found to be highly expressed in the hippocampal dentate gyrus of both rodents and humans, suggesting its potential involvement in the pathogenesis of schizophrenia [ 83 , 131 ].…”

Exploring orphan GPCRs in neurodegenerative diseases

“…Studies designing novel ligands for GPR85 continues and so far, a new inverse agonist has been identified ( Sakai et al, 2022 ). The association of GPR85 with learning and memory suggests a potential link to AD.…”

Molecular insights into orphan G protein‐coupled receptors relevant to schizophrenia

“…GPR85 activity could be beneficial in enhancing neuron proliferation and cognitive function—consequently inverse agonists have been sought. Due to a lack of constitutive activity, small molecules were screened in systems that expressed GPR85‐Gɑs fusion proteins (Sakai et al, 2022; Yanai et al, 2016). Nonselective inverse agonists of GPR85 were identified in GTPγ 35 S binding experiments, which were carried out in GPR85‐Gɑs expressing membranes from Sf9 insect cells (Sakai et al, 2022).…”

“…Due to a lack of constitutive activity, small molecules were screened in systems that expressed GPR85‐Gɑs fusion proteins (Sakai et al, 2022; Yanai et al, 2016). Nonselective inverse agonists of GPR85 were identified in GTPγ 35 S binding experiments, which were carried out in GPR85‐Gɑs expressing membranes from Sf9 insect cells (Sakai et al, 2022). Three compounds, 2g, 3h and 3i (Figure 3a), were identified with low micromolar potencies for inverse agonist activity at GPR85 but displayed similar potencies at GPR27 and GPR173.…”