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Review
. 2024 Mar;181(5):595-609.
doi: 10.1111/bph.16301. Epub 2024 Jan 8.

Orphan peptide and G protein-coupled receptor signalling in alcohol use disorder

Roberta Goncalves Anversa  1   2 , Xavier J Maddern  1   2 , Andrew J Lawrence  1   2 , Leigh C Walker  1   2
Affiliations
Review

Orphan peptide and G protein-coupled receptor signalling in alcohol use disorder

Roberta Goncalves Anversa et al. Br J Pharmacol. 2024 Mar.

Abstract

Neuropeptides and G protein-coupled receptors (GPCRs) have long been, and continue to be, one of the most popular target classes for drug discovery in CNS disorders, including alcohol use disorder (AUD). Yet, orphaned neuropeptide systems and receptors (oGPCR), which have no known cognate receptor or ligand, remain understudied in drug discovery and development. Orphan neuropeptides and oGPCRs are abundantly expressed within the brain and represent an unprecedented opportunity to address brain function and may hold potential as novel treatments for disease. Here, we describe the current literature regarding orphaned neuropeptides and oGPCRs implicated in AUD. Specifically, in this review, we focus on the orphaned neuropeptide cocaine- and amphetamine-regulated transcript (CART), and several oGPCRs that have been directly implicated in AUD (GPR6, GPR26, GPR88, GPR139, GPR158) and discuss their potential and pitfalls as novel treatments, and progress in identifying their cognate receptors or ligands.

Keywords: CART; GPCR; GPR135; GPR158; GPR26; GPR6; GPR88; alcohol use disorder; neuropeptide; orphan.

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Conflict of interest statement

All authors report no conflicts of interest.

Figures

FIGURE 1
FIGURE 1
Orphan neuropeptide and receptor expression in key brain regions implicated in alcohol use disorder, colour‐coded according to the three key phases of the addiction cycle (binge/intoxication, withdrawal/negative affect, preoccupation/anticipation). Amyg., amygdala; CART, cocaine‐ and amphetamine‐regulated transcript; Hab., habenula; Hipp., hippocampus; Hypo., hypothalamus; PFC, prefrontal cortex; VTA, ventral tegmental area.
FIGURE 2
FIGURE 2
Food and Drug Administration (FDA)‐approved compounds and compounds in clinical trial targeting non‐olfactory G protein‐coupled receptors (GPCRs). (a) One hundred and six (34.2%) deorphaned GPCRs currently have an FDA‐approved compound to target them, compared with only one (1.1%) oGPCR (left). Further, there are currently 57 (18.4%) deorphaned GPCRs that have a drug in ongoing clinical trials, compared with only two (2.3%) drugs targeting oGPCR (right). (b) Of the total number of FDA‐approved drugs targeting deorphaned GPCRs, 130 (27.1%) are for CNS indications, while there are no approved drugs targeting oGPCRs for CNS indications. Further, 15 (28.3%) of drugs in clinical trials targeting deorphaned GPCRs are for CNS indications, while there are no drugs currently in ongoing clinical trials targeting oGPCRs for CNS indications.
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