Orphan GPR52 as an emerging neurotherapeutic target

Saghir Ali; Pingyuan Wang; Ryan E. Murphy; John A. Allen; Jia Zhou

doi:10.1016/j.drudis.2024.103922

Orphan GPR52 as an emerging neurotherapeutic target

Saghir Ali, Pingyuan Wang, Ryan E. Murphy, John A. Allen, Jia Zhou

Pharmacology & Toxicology

Research output: Contribution to journal › Review article › peer-review

Abstract

GPR52 is a highly conserved, brain-enriched, G_s/olf-coupled orphan G protein-coupled receptor (GPCR) that controls various cyclic AMP (cAMP)-dependent physiological and pathological processes. Stimulation of GPR52 activity might be beneficial for the treatment of schizophrenia, psychiatric disorders and other human neurological diseases, whereas inhibition of its activity might provide a potential therapeutic approach for Huntington's disease. Excitingly, HTL0048149 (HTL’149), an orally available GPR52 agonist, has been advanced into phase I human clinical trials for the treatment of schizophrenia. In this concise review, we summarize the current understanding of GPR52 receptor distribution as well as its structure and functions, highlighting the recent advances in drug discovery efforts towards small-molecule GPR52 ligands. The opportunities and challenges presented by targeting GPR52 for novel therapeutics are also briefly discussed.

Original language	English (US)
Article number	103922
Journal	Drug Discovery Today
Volume	29
Issue number	4
DOIs	https://doi.org/10.1016/j.drudis.2024.103922
State	Published - Apr 2024

Keywords

GPR52
Huntington's disease
agonists
central nervous system disorders
drug discovery
orphan GPCR
schizophrenia

ASJC Scopus subject areas

Pharmacology
Drug Discovery

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10.1016/j.drudis.2024.103922

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title = "Orphan GPR52 as an emerging neurotherapeutic target",

abstract = "GPR52 is a highly conserved, brain-enriched, Gs/olf-coupled orphan G protein-coupled receptor (GPCR) that controls various cyclic AMP (cAMP)-dependent physiological and pathological processes. Stimulation of GPR52 activity might be beneficial for the treatment of schizophrenia, psychiatric disorders and other human neurological diseases, whereas inhibition of its activity might provide a potential therapeutic approach for Huntington's disease. Excitingly, HTL0048149 (HTL{\textquoteright}149), an orally available GPR52 agonist, has been advanced into phase I human clinical trials for the treatment of schizophrenia. In this concise review, we summarize the current understanding of GPR52 receptor distribution as well as its structure and functions, highlighting the recent advances in drug discovery efforts towards small-molecule GPR52 ligands. The opportunities and challenges presented by targeting GPR52 for novel therapeutics are also briefly discussed.",

keywords = "GPR52, Huntington's disease, agonists, central nervous system disorders, drug discovery, orphan GPCR, schizophrenia",

author = "Saghir Ali and Pingyuan Wang and Murphy, {Ryan E.} and Allen, {John A.} and Jia Zhou",

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AU - Ali, Saghir

AU - Wang, Pingyuan

AU - Murphy, Ryan E.

AU - Allen, John A.

AU - Zhou, Jia

PY - 2024/4

Y1 - 2024/4

N2 - GPR52 is a highly conserved, brain-enriched, Gs/olf-coupled orphan G protein-coupled receptor (GPCR) that controls various cyclic AMP (cAMP)-dependent physiological and pathological processes. Stimulation of GPR52 activity might be beneficial for the treatment of schizophrenia, psychiatric disorders and other human neurological diseases, whereas inhibition of its activity might provide a potential therapeutic approach for Huntington's disease. Excitingly, HTL0048149 (HTL’149), an orally available GPR52 agonist, has been advanced into phase I human clinical trials for the treatment of schizophrenia. In this concise review, we summarize the current understanding of GPR52 receptor distribution as well as its structure and functions, highlighting the recent advances in drug discovery efforts towards small-molecule GPR52 ligands. The opportunities and challenges presented by targeting GPR52 for novel therapeutics are also briefly discussed.

AB - GPR52 is a highly conserved, brain-enriched, Gs/olf-coupled orphan G protein-coupled receptor (GPCR) that controls various cyclic AMP (cAMP)-dependent physiological and pathological processes. Stimulation of GPR52 activity might be beneficial for the treatment of schizophrenia, psychiatric disorders and other human neurological diseases, whereas inhibition of its activity might provide a potential therapeutic approach for Huntington's disease. Excitingly, HTL0048149 (HTL’149), an orally available GPR52 agonist, has been advanced into phase I human clinical trials for the treatment of schizophrenia. In this concise review, we summarize the current understanding of GPR52 receptor distribution as well as its structure and functions, highlighting the recent advances in drug discovery efforts towards small-molecule GPR52 ligands. The opportunities and challenges presented by targeting GPR52 for novel therapeutics are also briefly discussed.

KW - GPR52

KW - Huntington's disease

KW - agonists

KW - central nervous system disorders

KW - drug discovery

KW - orphan GPCR

KW - schizophrenia

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Orphan GPR52 as an emerging neurotherapeutic target

Abstract

Keywords

ASJC Scopus subject areas

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