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Last update 08 May 2025

GPR88

Last update 08 May 2025

Basic Info

Synonyms

G protein coupled receptor 88, G protein-coupled receptor 88, G-protein coupled receptor 88

+ [4]

Introduction

Orphan G protein-coupled receptor implicated in a large repertoire of behavioral responses that engage motor activities, spatial learning, and emotional processing (By similarity). May play a role in the regulation of cognitive and motor function (By similarity). Couples with the heterotrimeric G protein complex of the G(i) subfamily, consisting of GNAI1, GNB1 and GNG2, thereby acting through a G(i)-mediated pathway (PubMed:35501348). Plays a role in the attenuation of D1 dopamine receptor (D1R)-mediated cAMP response in ciliated cells (PubMed:23936473). In non-ciliated cells, involved in the inhibition of the beta-2 adrenergic receptor (B2AR) response (PubMed:23936473).

Drugs associated with GPR88

GPR88 agonists(Acadia Pharmaceuticals)

Target

GPR88

Mechanism

GPR88 agonists

Active Org.

ACADIA Pharmaceuticals, Inc.

Originator Org.

ACADIA Pharmaceuticals, Inc.

Active Indication

Alzheimer Disease [+7]

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

GPR88 agonist(Bristol-Myers Squibb)

Target

GPR88

Mechanism

GPR88 agonists

Active Org.

Bristol Myers Squibb Co. [+1]

Originator Org.

Bristol Myers Squibb Co.

Active Indication

Nervous System Diseases

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

RTI-13951-33

Target

GPR88

Mechanism

GPR88 agonists

Active Org.

Research Triangle Institute

Originator Org.

Research Triangle Institute

Active Indication

Alcoholism

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with GPR88

100 Translational Medicine associated with GPR88

0 Patents (Medical) associated with GPR88

Literatures (Medical) associated with GPR88

01 Mar 2025·Neuropharmacology

GPR88 impairs the signaling of kappa opioid receptors in a heterologous system and in primary striatal neurons

Article

Author: Garrigós, Claudia ; Navarro, Gemma ; Lillo, Jaume ; Franco, Rafael ; Rivas-Santisteban, Rafael

The physiological role of GPR88, an orphan G protein-coupled receptor (GPCR) predominantly expressed in the striatum, remains unclear, despite its altered expression in parkinsonian animal models. GPR88 is known to interact with other GPCRs. Specifically, GPR88 expression inhibits signaling mediated by the μ-opioid receptor in cells coexpressing both receptors. The effect of GPR88 on the kappa-opioid receptor (KOR) is less understood. In this study, we examine the interaction between GPR88 and KOR, and the impact of GPR88 expression on KOR-mediated signaling in heterologous cells and primary striatal neurons. Bioluminescence resonance energy transfer and proximity ligation assays revealed an interaction between GPR88 and KOR. Functional assays showed that GPR88 antagonized the effects of U69,593, a selective KOR agonist, on forskolin-stimulated cAMP levels, β-arrestin-2 recruitment, and phosphorylation of extracellular signal-regulated kinases (ERK1/2) in HEK-293T cells coexpressing both receptors. In primary striatal neurons, GPR88 and KOR complexes were observed, with KOR activation effects enhanced when GPR88 expression was suppressed using RNA interference. These results suggest that GPR88 and KOR are coexpressed in striatal neurons, where GPR88 inhibits KOR activation. Notably, the GPR88-KOR heteromer was more prevalent in dopamine D₁-receptor-containing neurons of the direct pathway of the basal ganglia. Given the roles of KORs in dopamine release, motor function regulation, and pain and reward perception, the GPR88-KOR interaction warrants further investigation in the context of neuropathic pain, Parkinson's disease, and neuropsychiatric disorders.

11 Jul 2024·Journal of Medicinal Chemistry

Discovery of BI-9508, a Brain-Penetrant GPR88-Receptor-Agonist Tool Compound for In Vivo Mouse Studies

Article

Author: Recolet, Mandy ; Schlecker, Annette ; Faye, Vincent ; Eickmeier, Christian ; Young, Kyle ; Steinberg, Edith ; Hoerer, Stefan ; Fer, Mickael ; Frauli, Mélanie ; Klepp, Julian ; Kieffer, Brigitte L. ; Zinser, Alexander ; Lebrun, Louison ; Cui, Yunhai ; Halter, Célia ; Würstle, Klaus ; Breh-Schlanser, Petra ; Schann, Stephan ; Omrani, Azar ; Hoenke, Christoph ; Hucke, Oliver T. ; Heyer, Marjorie ; Amalric, Camille ; Schaeffer, Laurent ; Mayer, Stanislas ; Montel, Florian ; Baron, Luc ; Viloria, Mélanie ; Ben Hamida, Sami ; Franchet, Christel ; Darcq, Emmanuel ; Lotz, Noémie ; Arban, Roberto ; Joseph, Christophe

Decreased activity and expression of the G-protein coupled receptor GPR88 is linked to many behavior-linked neurological disorders. Published preclinical GPR88 allosteric agonists all have in vivo pharmacokinetic properties that preclude their progression to the clinic, including high lipophilicity and poor brain penetration. Here, we describe our attempts to improve GPR88 agonists' drug-like properties and our analysis of the trade-offs required to successfully target GPR88's allosteric pocket. We discovered two new GPR88 agonists: One that reduced morphine-induced locomotor activity in a murine proof-of-concept study, and the atropoisomeric BI-9508, which is a brain penetrant and has improved pharmacokinetic properties and dosing that recommend it for future in vivo studies in rodents. BI-9508 still suffers from high lipophilicity, and research on this series was halted. Because of its utility as a tool compound, we now offer researchers access to BI-9508 and a negative control free of charge via Boehringer Ingelheim's open innovation portal opnMe.com.

01 Jul 2024·British Journal of Pharmacology

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

Review

Author: Stewart, Gregory D ; Lu, Yao ; Hatzipantelis, Cassandra J ; Langmead, Christopher J

AbstractSchizophrenia remains a sizable socio‐economic 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 G protein‐coupled receptors (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, which demonstrated efficacy in some schizophrenia symptom domains. This provides renewed hope that effective schizophrenia treatment may lie 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 GPCRs: 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.LINKED ARTICLESThis article is part of a themed issue Therapeutic Targeting of G Protein‐Coupled Receptors: hot topics from the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists 2021 Virtual Annual Scientific Meeting. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.14/issuetoc

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