Discovery of a Potent, Selective, and Brain-Penetrant Small Molecule that Activates the Orphan Receptor GPR88 and Reduces Alcohol Intake

Jin, Chunyang; Decker, Ann M.; Makhijani, Viren H.; Besheer, Joyce; Darcq, Emmanuel; Kieffer, Brigitte L.; Maitra, Rangan

doi:10.1021/acs.jmedchem.8b00566

Cited by 29 publications

(65 citation statements)

References 38 publications

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“…Bmal1SKO and Per2SKO mice and their respective HET counterparts have only one functional copy of Gpr88 in MSNs since one copy is modified to drive Cre and GFP expression. Complete deletion of Gpr88 has been shown to augment alcohol intake in male mice [47,48], raising the possibility that the changes in alcohol consumption seen in striatal Bmal1SKO and striatal Per2SKO were due, at least in part, to a contributory effect of Gpr88 monoallelic expression. To study this possibility, we compared alcohol intake and preference between Gpr88+/+ mice (males, n = 7; females, n = 10) and Gpr88Cre/+ mice (males, n = 7; females, n = 12).…”

Section: Gpr88 Monoallelic Expression Does Not Affect Alcohol Intakementioning

confidence: 99%

Sexually dimorphic influence of the circadian clock geneBmal1in the striatum on alcohol intake

Zavalía¹,

Schöttner²,

Goldsmith³

et al. 2020

Preprint

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SummaryThe clock gene Bmal1 plays an obligatory role in the generation of circadian rhythms in gene expression, physiology, and behavior in mammals [1–4]. In mice, perturbations in Bmal1 expression in the brain are associated with loss of circadian rhythmicity and various physiological and behavioral disturbances, including disrupted sleep architecture and deficits in cognitive and affective behaviors [5–14]. Gene association studies in both humans and animals suggest that Bmal1 may also play a role in the control of appetitive behaviors such as alcohol preference and consumption [15–19]. Although there is evidence that genes that interact with Bmal1 in the molecular circadian clock, such as Per2 and Clock influence alcohol intake and preference [15, 20–23], experimental evidence of a causal role of Bmal1 is lacking. In addition, the specific brain regions where Bmal1 might affect alcohol consumption are not known. We investigated voluntary alcohol consumption in conditional knockout mice that lack BMAL1 protein exclusively in the striatum, which is an important structure in the control of alcohol intake and preference [24–29]. Particular emphasis was attributed to the investigation of male and female mice because of known sex differences in alcohol intake and preference [30–32], and the impact of a sexually dimorphic constitution of circadian clocks on behavior [33, 34]. We found that deletion of BMAL1 from the principal medium spiny neurons (MSNs) of the striatum significantly altered voluntary alcohol intake and preference, without affecting total fluid intake, sucrose preference, body weight, or circadian rhythms in behavior. Strikingly, there were major sex differences in the effect of striatal BMAL1 deletion on alcohol consumption. While striatal BMAL1 deletion augmented alcohol intake and preference in males, the same deletion suppressed intake and preference in females. Interestingly, striatal deletion of PER2, a clock gene that interacts with Bmal1 in the circadian clock, and which has been shown to limit alcohol consumption in mice [22], mimicked the effect of striatal BMAL1 deletion, albeit only in males. Together, our results reveal that BMAL1 in MSNs of the striatum plays a sexually dimorphic role in the control of alcohol intake in mice, restraining consumption in males, possibly by interacting with PER2, and promoting intake in females, independently of PER2. We therefore hypothesize that a sex-specific mechanism in the function of BMAL1 in MSNs of the striatum regulates differences between male and female mice in the propensity to consume alcohol.

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Section: Gpr88 Monoallelic Expression Does Not Affect Alcohol Intakementioning

confidence: 99%

Sexually dimorphic influence of the circadian clock geneBmal1in the striatum on alcohol intake

Zavalía¹,

Schöttner²,

Goldsmith³

et al. 2020

Preprint

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“…Despite extensive efforts towards the deorphanization of GPR88, the endogenous ligand(s) remains unknown [ 193 , 194 , 195 , 196 ]. Nonetheless, the first synthetic agonists for this oGPCR have been identified, while high affinity antagonists are still unavailable [ 193 , 195 , 197 ]. Although GPR88 signaling properties still lack a detailed analysis, it was shown that the pharmacological stimulation of GPR88 led to the activation of G protein heterotrimers of the Gi/o/z family, both in native and heterologous expression systems [ 88 , 196 , 197 ].…”

Section: Systematic Analysis Of Ogpcrs In Anxiety and Mood Disordementioning

confidence: 99%

“…Nonetheless, the first synthetic agonists for this oGPCR have been identified, while high affinity antagonists are still unavailable [ 193 , 195 , 197 ]. Although GPR88 signaling properties still lack a detailed analysis, it was shown that the pharmacological stimulation of GPR88 led to the activation of G protein heterotrimers of the Gi/o/z family, both in native and heterologous expression systems [ 88 , 196 , 197 ]. The striatal enrichment of GPR88 inspired a number of studies that linked it to neurophysiological processes, such as motor control, reward behaviors, cognitive functions, and neuropsychiatric disorders resulting from deficits in striatal function [ 88 , 89 , 191 , 198 , 199 , 200 ].…”

Section: Systematic Analysis Of Ogpcrs In Anxiety and Mood Disordementioning

confidence: 99%

Orphan G Protein Coupled Receptors in Affective Disorders

Watkins

Orlandi

2020

Genes

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G protein coupled receptors (GPCRs) are the main mediators of signal transduction in the central nervous system. Therefore, it is not surprising that many GPCRs have long been investigated for their role in the development of anxiety and mood disorders, as well as in the mechanism of action of antidepressant therapies. Importantly, the endogenous ligands for a large group of GPCRs have not yet been identified and are therefore known as orphan GPCRs (oGPCRs). Nonetheless, growing evidence from animal studies, together with genome wide association studies (GWAS) and post-mortem transcriptomic analysis in patients, pointed at many oGPCRs as potential pharmacological targets. Among these discoveries, we summarize in this review how emotional behaviors are modulated by the following oGPCRs: ADGRB2 (BAI2), ADGRG1 (GPR56), GPR3, GPR26, GPR37, GPR50, GPR52, GPR61, GPR62, GPR88, GPR135, GPR158, and GPRC5B.

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“…Later, an in vivo study further verified that administration of GPR88 agonists can significantly reduce alcohol self-administration and alcohol intake in a dose-dependent manner (more details in section 4.1). 61…”

Section: Gpr88 As a Potential Therapeutic Target For Human Cns Diseasesmentioning

confidence: 99%

Orphan Receptor GPR88 as an Emerging Neurotherapeutic Target

Mao

et al. 2018

ACS Chem. Neurosci.

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Although G protein-coupled receptors (GPCRs) are recognized as pivotal drug targets involved in multiple physiological and pathological processes, the majority of GPCRs including orphan GPCRs (oGPCRs) are unexploited. GPR88, a brain-specific oGPCR with particularly robust expression in the striatum, regulates diverse brain and behavioral functions, including cognition, mood, movement control, and reward-based learning, and is thus emerging as a novel drug target for central nervous system disorders including schizophrenia, Parkinson’s disease, anxiety, and addiction. Nevertheless, no effective GPR88 synthetic ligands have yet entered into clinical trials, and GPR88 endogenous ligands remain unknown. Despite the recent discovery and early stage study of several GPR88 agonists, such as 2-PCCA, RTI-13951–33, and phenylglycinol derivatives, further research into GPR88 pharmacology, medicinal chemistry, and chemical biology is urgently needed to yield structurally diversified GPR88-specific ligands. Drug-like pharmacological tool function and relevant signaling elucidation will also accelerate the evaluation of this receptor as a viable neurotherapeutic target.

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Discovery of a Potent, Selective, and Brain-Penetrant Small Molecule that Activates the Orphan Receptor GPR88 and Reduces Alcohol Intake

Cited by 29 publications

References 38 publications

Sexually dimorphic influence of the circadian clock geneBmal1in the striatum on alcohol intake

Sexually dimorphic influence of the circadian clock geneBmal1in the striatum on alcohol intake

Orphan G Protein Coupled Receptors in Affective Disorders

Orphan Receptor GPR88 as an Emerging Neurotherapeutic Target

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