S39. Gpr139 an Ophan GPCR Affecting Negative Domains of Schizophrenia

Abstract

BackgroundIndividuals with schizophrenia fail to appropriately use negative feedback to guide learning. These learning deficits are thought to arise from abnormalities in midbrain dopamine activity. The habenula is a well conserved paired structure that sits in the midline, adjacent to the third ventricle, and dorsal and posterior to the thalamus. Classic studies have shown that it is part of the reward pathway and functions with dopamine neurons in the ventral tegmental area (VTA) to mediate reward related signals, specifically aversive and negative stimulus (Hikosaka, 2010). Several studies point to pathology in the habenula as contributing to schizophrenia (Sandyk, 1992; Caputo et al., 1998; Shepard et al., 2006). Despite the many studies on the habenula, the precise function of the habenula remains unclear. Here we describe functional consequences of regulation of GPR139 an orphan GPCR that is specifically expressed in the CNS and enriched in the habenula (Matsuo et al., 2005) in mouse models of domain of schizophrenia.MethodsSpecific expression of mouse GPR139 in the habenula was evaluated using bacterial artificial chromosome translating ribosome affinity purification (bacTRAP) and confirmed by immunohistochemistry. GPR139-/- mice were generated by removal of a 736bp region encoding the seven transmembrane domain (7TM) domain. Knockout animals were maintained inbred on a 129/SvEv background and evaluated in behavioral models that reflect aspects of negative symptoms. High throughput screen (HTS) for small molecules was performed. We expressed full length GPR139 into CHO cells and screened a 600K library using a calcium assay to identify small molecule agonist. Hits were identified and physical properties optimized to produce a molecule suitable for in vivo evaluation. GPR139 agonist was testedin vivo in social interaction in Poly(I:C) and cognitive test in subchronic PCP, models of schizophrenia.ResultsUsing bacTRAP we observed enriched expression of GPR139 in substance P positive- cells of the medial habenula. This expression was confirmed with immunohistochemistry. To determine if GPR139 regulates the known role of the habenula in learning, motivation, and social behaviour, GPR139 -/- animals were generated and phenotyped. These animals appeared normal and performed comparably to wild-type animals in a range of standard tasks. However, they were significantly impaired in models that reflect aspects of negative symptoms such as progressive ratio (Killeen et al., 2009; Heath et al., 2016), a measure of motivation and nest-building (Pedersen et al., 2014; Nakajima et al., 2013), a model of self-neglect. Furthermore, these animals showed deficits in novel object recognition model of working memory (Antunes and Biala, 2012). The small molecule agonist was observed to reverse deficits in models of schizophrenia including cognition in a subchronic PCP induced attentional set-shifting paradigm (Birrell and Brown, 2000) and social interaction in the Poly(I:C) maternal model (Meyer et al., 2008; Bitanihirwe...

GPR139 and Dopamine D2 Receptor Co-express in the Same Cells of the Brain and May Functionally Interact

“…Interestingly, in light of the DRD2/GPR139 mRNAs co-expression found in the mesolimbic pathway (projects from VTA to nucleus accumbens and Tu) (Ikemoto, 2010), a recent preclinical study using the selective GPR139 agonist JNJ-63533054 showed that GPR139 receptor activation reverses key addiction-like behaviors in dependent animals (Kononoff et al, 2018). Another GPR139 agonist 4-oxo-3,4-dihydro-1,2,3-benzotriazine has been reported to improve social withdrawal in a preclinical model of the negative symptom of schizophrenia (Atienza et al, 2018), involving the mesocortical pathway (initiate from VTA but instead project to the prefrontal cortex) (Ekhtiari and Paulus, 2016). A recent study reported that the GPR139 agonist TC-O 9311 (structurally identical to compound 1a used in this study) protected primary mesencephalic dopamine neurons against 1-methyl-4-phenylpyridinium (MPP+)-mediated degeneration, indicating a potential role of GPR139 in neuroprotection and Parkinson’s disease (Bayer Andersen et al, 2016).…”

“…Despite the availability of several selective agonists, the physiological function of GPR139 remains elusive. Its potential role in addiction (Kononoff et al, 2018), Parkinson’s disease (Bayer Andersen et al, 2016), locomotor activity (Liu et al, 2015), and schizophrenia (Atienza et al, 2018) has been suggested. L-Trp and L-Phe are the precursors for serotonin and dopamine biosynthesis, respectively, which are neurotransmitters implicated in mood regulation (Toker et al, 2010; Anjema et al, 2011; ten Hoedt et al, 2011; Jenkins et al, 2016).…”

Translation-Focused Approaches to GPCR Drug Discovery for Cognitive Impairments Associated with Schizophrenia

“…GPR139 knockout mice show impaired episodic-like memory, working memory, and motivation, while a GPR139 agonist reverses impaired cognitive flexibility in mouse models of CIAS. 233 A phase II proof-of-concept clinical trial was completed in September 2019 assessing the procognitive and motivational efficacy of the GPR139 agonist TAK-041 as an add-on treatment for schizophrenia patients with CIAS. While results are yet to be posted, TAK-041 remains an active program.…”

Mutagenesis of GPR139 reveals ways to create gain or loss of function receptors

“…Bayer Andersen et al have recently reported that the GPR139 agonist TC‐O 9311 protected primary mesencephalic dopamine neurons against 1‐methyl‐4‐phenylpyridinium (MPP+)‐mediated degeneration, indicating a potential role of GPR139 in neuroprotection and Parkinson's disease . Another GPR139 agonist, 4‐oxo‐3,4‐dihydro‐1,2,3‐benzotriazine, has been reported to improve social withdrawal …”

“…11 Another GPR139 agonist, 4-oxo-3,4-dihydro-1,2,3-benzotriazine, has been reported to improve social withdrawal. 12 From a structural perspective, Kaushik and Sahi reported a three dimensional structure prediction and molecular dynamics simulation of GPR139 model. Further structure-based virtual screening was applied and several active site residues of GPR139, including Tyr32, Glu105, Glu108, and Tyr192, have been identified as potential ligand binding sites for inhibition of protein dimerization and receptor activity.…”