MRGPRX2

Summary

MRGPRX2 (MAS related GPR family member X2, HGNC:17983) is a protein-coding gene on chromosome 11p15.1, encoding Mas-related G-protein coupled receptor member X2 (Q96LB1). Mast cell-specific G protein-coupled receptor for basic secretagogues, which regulates mast cell degranulation and itch-related hypersensitivity reactions.

Enables G protein-coupled receptor activity and neuropeptide binding activity. Involved in mast cell degranulation and positive regulation of cytokinesis. Predicted to be located in membrane. Predicted to be active in plasma membrane.

Source: NCBI Gene 117194 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 45 total
• Druggable target: yes — 16 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_054030

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17983
Approved symbol	MRGPRX2
Name	MAS related GPR family member X2
Location	11p15.1
Locus type	gene with protein product
Status	Approved
Aliases	MRGX2
Ensembl gene	ENSG00000183695
Ensembl biotype	protein_coding
OMIM	607228
Entrez	117194

Gene structure

Transcript identifiers

Ensembl transcripts: 1 — 1 protein_coding

ENST00000329773

RefSeq mRNA: 2 — MANE Select: NM_054030 NM_001303615, NM_054030

CCDS: CCDS7847

Canonical transcript exons

ENST00000329773 — 2 exons

Exon	Start	End
ENSE00001311659	19054455	19056427
ENSE00001367104	19060619	19060717

Expression profiles

Bgee: expression breadth broad, 52 present calls, max score 93.54.

FANTOM5 (CAGE): breadth tissue_specific, TPM avg 2.2102 / max 1330.4489, expressed in 31 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
118983	2.0189	30
118982	0.1675	6
118980	0.0155	3
118981	0.0083	3

Top tissues by expression

236 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
male germ line stem cell (sensu Vertebrata) in testis	CL:0000089 ∩ UBERON:0000473	93.54	gold quality
skin of abdomen	UBERON:0001416	55.76	gold quality
skin of leg	UBERON:0001511	53.76	gold quality
zone of skin	UBERON:0000014	52.88	gold quality
subcutaneous adipose tissue	UBERON:0002190	49.78	gold quality
lower esophagus	UBERON:0013473	46.90	gold quality
lower esophagus muscularis layer	UBERON:0035833	46.83	gold quality
rectum	UBERON:0001052	46.75	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	46.68	gold quality
urinary bladder	UBERON:0001255	45.33	gold quality
buccal mucosa cell	CL:0002336	45.04	gold quality
lower esophagus mucosa	UBERON:0035834	44.94	silver quality
fundus of stomach	UBERON:0001160	43.78	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	43.37	gold quality
nipple	UBERON:0002030	43.21	gold quality
granulocyte	CL:0000094	42.98	silver quality
adipose tissue	UBERON:0001013	42.60	gold quality
secondary oocyte	CL:0000655	42.57	gold quality
sural nerve	UBERON:0015488	42.23	gold quality
vagina	UBERON:0000996	41.78	gold quality
vastus lateralis	UBERON:0001379	41.41	gold quality
quadriceps femoris	UBERON:0001377	41.37	gold quality
superficial temporal artery	UBERON:0001614	41.33	gold quality
inferior vagus X ganglion	UBERON:0005363	41.22	gold quality
esophagus	UBERON:0001043	41.19	gold quality
palpebral conjunctiva	UBERON:0001812	41.10	gold quality
mucosa of stomach	UBERON:0001199	41.03	silver quality
mucosa of paranasal sinus	UBERON:0005030	40.98	gold quality
amniotic fluid	UBERON:0000173	40.69	gold quality
smooth muscle tissue	UBERON:0001135	40.61	silver quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	4.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

53 targeting MRGPRX2, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4747-5P	100.00	67.90	2681
HSA-MIR-5196-5P	100.00	67.98	2761
HSA-MIR-4533	100.00	69.48	2758
HSA-MIR-548AW	99.99	72.57	3559
HSA-MIR-8068	99.98	73.85	2376
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-545-3P	99.95	70.74	2783
HSA-MIR-4525	99.94	64.38	675
HSA-MIR-5010-5P	99.94	64.11	705
HSA-MIR-5582-3P	99.86	72.48	4221
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-548AG	99.77	69.25	1492
HSA-MIR-4524A-3P	99.72	66.85	2406
HSA-MIR-548M	99.70	68.87	1749
HSA-MIR-548AI	99.69	69.24	1494
HSA-MIR-548BA	99.69	69.14	1514
HSA-MIR-570-5P	99.69	69.24	1494
HSA-MIR-4527	99.66	67.43	714
HSA-MIR-452-5P	99.65	69.63	1762
HSA-MIR-4676-3P	99.65	69.31	1733
HSA-MIR-892C-3P	99.65	69.38	1745
HSA-MIR-6503-5P	99.62	66.96	597
HSA-MIR-6073	99.60	70.36	793
HSA-MIR-7159-5P	99.53	72.12	2472
HSA-MIR-543	99.52	69.03	2595
HSA-MIR-671-5P	99.52	67.11	1277
HSA-MIR-12123	99.52	71.79	2990
HSA-MIR-1324	99.46	66.57	1302

Literature-anchored findings (GeneRIF, showing 40)

• cortistatin-14 shown to be a high affinity ligand for G protein coupled receptor MrgX2 which is expressed in dorsal root ganglion (PMID:12915402)
• MRGX2 amino acid substitutions may alter the interactions between MRGX2 protein and its ligand, thus, potentially led to adaptive changes of the pain-perception-related nervous system during human evolution. (PMID:15862286)
• Mas, MrgD, and MRG mediated Ang IV-stimulated AA release that was highest for Mas. While Ang III activated Mas and MrgX2, Ang II stimulated AA release via Mas and MRG. (PMID:18636314)
• identified MrgX2 as a novel G protein-coupled receptor for the antibacterial peptide LL-37 and demonstrated that unlike most G protein-coupled receptors it is resistant to agonist-induced receptor phosphorylation, desensitization, and internalization. (PMID:22069323)
• Ectopic expression of MrgX2 in rat basophilic leukemia RBL-2H3 cells and murine bone marrow mast cells renders these cells responsive to human beta-defensin for degranulation. (PMID:23698749)
• contributes to larger and longer lasting wheal reactions to intradermally injected neuropeptides in patients with chronic urticaria (PMID:24954276)
• MRGX2 is related to nociception, adrenal gland secretion and mast cell degranulation. (Review) (PMID:26106044)
• data suggest that mast cells play important roles in both gingival homeostasis and periodontal disease by orchestrating an interaction between gingival epithelial cells and neutrophils via MRGPRX2-mediated degranulation (PMID:28694291)
• these peptides are identified as fragments of albumin. The isolated fragments activate MRGPRX2 and degranulate MRGPRX2 expressing LAD 2 cells in dose-dependent manner. The isolated basic peptides generated from human albumin are able to degranulate mast cells via the MRGPRX2. (PMID:28844982)
• the present study demonstrates that FceRI and MRGPRX2 function can be inversely regulated by SCF in an acute scenario, suggesting that the signaling requirements differ profoundly between the routes. (PMID:28859248)
• The results showed a kind of mechanism that sinomenine-induced anaphylactoid reactions were mediated by MRGPRX2 via activating PLC molecular signaling pathways to provoke mast cells Ca(2+) mobilization and degranulation. (PMID:28987593)
• Study reports that a cysteine protease mucunain, active component of cowhage (itch-inducing spicules or trichomes that cover the seedpods of the tropical plant Mucuna pruriens) that is routinely used in human studies of histamine-independent itch, activates human MRGPRX1 and MRGPRX2 receptors and induces degranulation of human mast cells. (PMID:28988117)
• Low levels of MRGPRX2 were detected in non-asthma lung mast cells, but its expression was significantly up-regulated in asthma lung mast cells. (PMID:29295703)
• The authors discuss the possibility that MRGPRX2 responds to various as-yet-unidentified endogenous ligands that have specific characteristics, and propose that MRGPRX2 plays an important role in regulating inflammatory responses to endogenous harmful stimuli, such as protein breakdown products released from damaged or dying cells. (PMID:29484687)
• Isoliquiritigenin (ISL) dose dependently inhibits C48/80-induced MRGPRX2-expressing HEK293 cell activation. ISL inhibits IgE-independent allergy via the Mrgprx2 pathway. (PMID:29684393)
• Four natural MRGPRX2 variants, G165E (rs141744602), D184H (rs372988289), W243R (rs150365137), and H259Y (rs140862085) failed to respond to any of the ligands tested. (PMID:29794017)
• MRGPRX2 is a candidate for consideration in non-IgE-mediated allergic reactions to some perioperative drugs, reinforcing its role in mast cell responses and their pathophysiology. (PMID:30072729)
• this study shows that mast cell-mediated hypersensitivity to fluoroquinolone is MRGPRX2 dependent (PMID:30856392)
• Gold chloride induces a pseudo-allergic reaction via MRGPRX2 both in vitro and in vivo. (PMID:31076078)
• Study investigated whether thimerosal induces pseudo-allergic reactions directly through MrgprB2 and MRGPRX2 on mast cells in vitro and in vivo and revealed that MrgprB2 mediates thimerosal-induced mast cell degranulation and pseudo-allergic reaction in mice. MRGPRX2 may be a key contributor to human contact dermatitis. (PMID:31558225)
• Clinical significance of serum MRGPRX2 as a new biomarker in allergic asthma. (PMID:31605391)
• Conserved residues in TM6 (I225) and TM7 (Y279) of MRGPRX2 are essential for SP-induced Ca2+ mobilization and mast cell activation by substance P. (PMID:31652731)
• The pseudoallergen receptor MRGPRX2 on peripheral blood basophils and eosinophils: Expression and function. (PMID:32003863)
• Store-Operated Calcium Entry via STIM1 Contributes to MRGPRX2 Induced Mast Cell Functions. (PMID:32038646)
• MRGPRX2 and Immediate Drug Hypersensitivity: Insights From Cultured Human Mast Cells. (PMID:32732181)
• MRGPRX2 signals its importance in cutaneous mast cell biology: Does MRGPRX2 connect mast cells and atopic dermatitis? (PMID:32866307)
• MRGPRX2 Is the Codeine Receptor of Human Skin Mast Cells: Desensitization through beta-Arrestin and Lack of Correlation with the FcepsilonRI Pathway. (PMID:33058860)
• Immunoglobulin E cross-linking or MRGPRX2 activation: clinical insights from rocuronium hypersensitivity. (PMID:33153719)
• MRGPRX2 is critical for clozapine induced pseudo-allergic reactions. (PMID:33327824)
• Inflamed Ulcerative Colitis Regions Associated With MRGPRX2-Mediated Mast Cell Degranulation and Cell Activation Modules, Defining a New Therapeutic Target. (PMID:33421512)
• Thymic Stromal Lymphopoietin Promotes MRGPRX2-Triggered Degranulation of Skin Mast Cells in a STAT5-Dependent Manner with Further Support from JNK. (PMID:33429916)
• MRGPRX2 Activation by Rocuronium: Insights from Studies with Human Skin Mast Cells and Missense Variants. (PMID:33467419)
• A group of cationic amphiphilic drugs activates MRGPRX2 and induces scratching behavior in mice. (PMID:33617860)
• Human Mast Cell Line HMC1 Expresses Functional Mas-Related G-Protein Coupled Receptor 2. (PMID:33790895)
• Cytokines Stimulated by IL-33 in Human Skin Mast Cells: Involvement of NF-kappaB and p38 at Distinct Levels and Potent Co-Operation with FcepsilonRI and MRGPRX2. (PMID:33808264)
• Multifaceted MRGPRX2: New insight into the role of mast cells in health and disease. (PMID:33957166)
• Substance P Serves as a Balanced Agonist for MRGPRX2 and a Single Tyrosine Residue Is Required for beta-Arrestin Recruitment and Receptor Internalization. (PMID:34070125)
• Expression of MRGPRX2 in skin mast cells of patients with maculopapular cutaneous mastocytosis. (PMID:34182161)
• Cytokine Stimulation by MRGPRX2 Occurs with Lower Potency than by FcepsilonRI Aggregation but with Similar Dependence on the Extracellular Signal-Regulated Kinase 1/2 Module in Human Skin Mast Cells. (PMID:34329659)
• A paper-based ELISA for rapid sensitive determination of anaphylaxis-related MRGPRX2 in human peripheral blood. (PMID:34597615)

Cross-species orthologs

26 orthologs

Organism	Symbol	Gene ID
mus_musculus	Mrgprb2	ENSMUSG00000050425
mus_musculus	Mrgpra1	ENSMUSG00000050650
mus_musculus	Mrgprb8	ENSMUSG00000050870
mus_musculus	Mrgpra6	ENSMUSG00000052303
mus_musculus	Mrgpra4	ENSMUSG00000067173
mus_musculus	Mrgprb3	ENSMUSG00000070546
mus_musculus	Mrgprb1	ENSMUSG00000070547
mus_musculus	Mrgprb4	ENSMUSG00000070550
mus_musculus	Mrgprb5	ENSMUSG00000070551
mus_musculus	Mrgprx1	ENSMUSG00000070552
mus_musculus	Mrgprx2	ENSMUSG00000074109
mus_musculus	Mrgpra9	ENSMUSG00000074111
mus_musculus	Mrgpra3	ENSMUSG00000078698
mus_musculus	Mrgpra2a	ENSMUSG00000093973
mus_musculus	Mrgpra2b	ENSMUSG00000096719
rattus_norvegicus	Mrgprx3	ENSRNOG00000014227
rattus_norvegicus	Mrgprx1	ENSRNOG00000014242
rattus_norvegicus	Mrgprb3l	ENSRNOG00000014266
rattus_norvegicus	Mrgprb5	ENSRNOG00000022703
rattus_norvegicus	Mrgprx2l	ENSRNOG00000022729
rattus_norvegicus	Mrgprb3	ENSRNOG00000028982
rattus_norvegicus	Mrgprb4	ENSRNOG00000033021
rattus_norvegicus	Mrgprb2	ENSRNOG00000037156
rattus_norvegicus	Mrgprb13	ENSRNOG00000074277
rattus_norvegicus		ENSRNOG00000081169
rattus_norvegicus		ENSRNOG00000084911

Paralogs (10): MAS1 (ENSG00000130368), MRGPRX1 (ENSG00000170255), MRGPRF (ENSG00000172935), MRGPRD (ENSG00000172938), GPR152 (ENSG00000175514), MRGPRX4 (ENSG00000179817), MRGPRX3 (ENSG00000179826), MRGPRG (ENSG00000182170), MRGPRE (ENSG00000184350), MAS1L (ENSG00000204687)

Protein

Protein identifiers

Mas-related G-protein coupled receptor member X2 — Q96LB1 (reviewed: Q96LB1)

All UniProt accessions (1): Q96LB1

UniProt curated annotations — full annotation on UniProt →

Function. Mast cell-specific G protein-coupled receptor for basic secretagogues, which regulates mast cell degranulation and itch-related hypersensitivity reactions. A secretagogue is an agent that promotes the secretion of hormones, neurohormones, chemical neurotransmitters or other compounds synthesized and secreted by cells. Basic secretagogues comprise a set of cationic amphiphilic drugs, as well as endo- or exogenous peptides, consisting of a basic head group and a hydrophobic core. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors, such as adenylate cyclase. MRGPRX2 is both coupled to G(q) and G(i) G proteins: G(q) coupling activates phospholipase C-beta, releasing diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3) second messengers, while G(i) coupling mediates inhibition of adenylate cyclase activity. Recognizes and binds small molecules containing a cyclized tetrahydroisoquinoline (THIQ), such as non-steroidal neuromuscular blocking drugs (NMBDs), including tubocurarine and atracurium. In response to these compounds, mediates pseudo-allergic reactions characterized by histamine release, inflammation and airway contraction. Acts as a receptor for substance P, a basic secretagogue neuropeptide released from the terminals of specific sensory nerves, initiating a signaling that mediates neurogenic inflammation and pain. Neurogenic inflammation includes mast cell activation, recruitment of immune cells and release of inflammatory mediators, such as cytokines and chemokines. The inflammatory response can then activate or sensitize nociceptors, promoting pain. Acts as a receptor for a number of other ligands, including peptides and alkaloids, such as cortistatin-14, proadrenomedullin peptides PAMP-12 and, at lower extent, PAMP-20, antibacterial protein LL-37, PMX-53 peptide, beta-defensins, and complanadine A. Also acts as a receptor for opioids, such as (-)- and (+)-morphine, hydrocodone, sinomenine, dextromethorphan, dynorphin A, dynorphin B, and alpha- and beta-neoendorphin, promoting mast cell degranulation.

Subcellular location. Cell membrane.

Tissue specificity. Mainly expressed in mast cells. Has a limited expression profile, both peripheral and within the central nervous system, with highest levels in dorsal root ganglion. Detected in blood vessels, scattered lymphocytes, and gastrointestinal ganglia (at protein level).

Activity regulation. Activated by the selective small-molecule agonist ZINC-3573. Inhibited by the selective small-molecule antagonist ZINC16991592. Activated by the basic secretagogue compound 48/80 (C48/80).

Similarity. Belongs to the G-protein coupled receptor 1 family. Mas subfamily.

RefSeq proteins (2): NP_001290544, NP_473371* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000276	GPCR_Rhodpsn	Family
IPR017452	GPCR_Rhodpsn_7TM	Domain
IPR026234	MRGPCRFAMILY	Family

Pfam: PF00001

UniProt features (52 total): mutagenesis site 11, helix 10, topological domain 8, transmembrane region 7, sequence variant 6, strand 4, turn 3, disulfide bond 2, chain 1

Structure

Experimental structures (PDB)

14 structures.

PDB	Method	Resolution (Å)
7S8L	ELECTRON MICROSCOPY	2.45
7S8M	ELECTRON MICROSCOPY	2.54
7S8O	ELECTRON MICROSCOPY	2.58
7VV5	ELECTRON MICROSCOPY	2.76
7VUY	ELECTRON MICROSCOPY	2.84
7VUZ	ELECTRON MICROSCOPY	2.89
7S8N	ELECTRON MICROSCOPY	2.9
7VDH	ELECTRON MICROSCOPY	2.9
7VV3	ELECTRON MICROSCOPY	2.97
7VV4	ELECTRON MICROSCOPY	2.97
7VDM	ELECTRON MICROSCOPY	2.98
7VDL	ELECTRON MICROSCOPY	3.22
7VV6	ELECTRON MICROSCOPY	3.3
7VV0	ELECTRON MICROSCOPY	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q96LB1-F1	81.81	0.43

Antibody-complex structures (SAbDab): 11 — 7S8L, 7S8M, 7S8N, 7S8O, 7VDH, 7VDL, 7VDM, 7VUY, 7VUZ, 7VV3, 7VV5

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Disulfide bonds (2): 26–258, 168–180

Mutagenesis-validated functional residues (11):

Position	Phenotype
94	abolished g protein-coupled receptor signaling in response to substance p-binding.
127	decreased g(i)-coupled signaling.
138	decreased g(i)-coupled signaling.
164	decreased g protein-coupled receptor signaling.
165	abolished g protein-coupled receptor signaling in response to substance p-binding.
168	abolished g protein-coupled receptor signaling.
170	decreased g protein-coupled receptor signaling in response to cortistatin-14 binding.
180	abolished g protein-coupled receptor signaling.
184	decreased g protein-coupled receptor signaling.
214	decreased g(i)-coupled signaling.
243	abolished g protein-coupled receptor signaling in response to cortistatin-14 binding.

Function

Pathways and Gene Ontology

Reactome pathways

0 pathways

MSigDB gene sets: 84 (showing top): GOBP_MYELOID_LEUKOCYTE_MIGRATION, GOBP_POSITIVE_REGULATION_OF_CYTOKINE_PRODUCTION, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_LEUKOCYTE_MEDIATED_IMMUNITY, GOBP_REGULATION_OF_LEUKOCYTE_MIGRATION, GOBP_MULTICELLULAR_ORGANISMAL_RESPONSE_TO_STRESS, GOBP_CELL_ACTIVATION_INVOLVED_IN_IMMUNE_RESPONSE, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_LEUKOCYTE_MIGRATION, GOBP_SENSORY_PERCEPTION_OF_PAIN, GOBP_MAST_CELL_ACTIVATION, GOBP_EXOCYTOSIS, GOBP_POSITIVE_REGULATION_OF_NEUTROPHIL_MIGRATION, GOBP_POSITIVE_REGULATION_OF_LEUKOCYTE_MIGRATION, GOBP_RESPONSE_TO_PAIN

GO Biological Process (13): positive regulation of cytokine production (GO:0001819), G protein-coupled receptor signaling pathway (GO:0007186), adenylate cyclase-inhibiting G protein-coupled receptor signaling pathway (GO:0007193), phospholipase C-activating G protein-coupled receptor signaling pathway (GO:0007200), sensory perception of pain (GO:0019233), sleep (GO:0030431), positive regulation of cytokinesis (GO:0032467), positive regulation of chemokine production (GO:0032722), mast cell degranulation (GO:0043303), mast cell activation (GO:0045576), response to pain (GO:0048265), positive regulation of neutrophil migration (GO:1902624), signal transduction (GO:0007165)

GO Molecular Function (4): G protein-coupled receptor activity (GO:0004930), G protein-coupled opioid receptor activity (GO:0004985), neuropeptide binding (GO:0042923), mast cell secretagogue receptor activity (GO:1990595)

GO Cellular Component (2): plasma membrane (GO:0005886), membrane (GO:0016020)

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
G protein-coupled receptor activity	3
G protein-coupled receptor signaling pathway	2
cytokine production	1
regulation of cytokine production	1
positive regulation of gene expression	1
positive regulation of multicellular organismal process	1
signal transduction	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase inhibitor activity	1
phospholipase C activator activity	1
sensory perception	1
multicellular organismal process	1
cytokinesis	1
regulation of cytokinesis	1
positive regulation of cell division	1
positive regulation of cell cycle process	1
positive regulation of cytokine production	1
chemokine production	1
regulation of chemokine production	1
mast cell activation involved in immune response	1
mast cell mediated immunity	1
lysosome localization	1
leukocyte degranulation	1
establishment of organelle localization	1
myeloid leukocyte activation	1
multicellular organismal response to stress	1
positive regulation of leukocyte migration	1
regulation of neutrophil migration	1
neutrophil migration	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
transmembrane signaling receptor activity	1
G protein-coupled opioid receptor signaling pathway	1
peptide binding	1
membrane	1
cell periphery	1
cellular anatomical structure	1

Protein interactions and networks

STRING

458 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
MRGPRX2	CAMP	P49913	976
MRGPRX2	CORT	O00230	968
MRGPRX2	TAC1	P20366	888
MRGPRX2	NPFF	O15130	852
MRGPRX2	SST	P01166	696
MRGPRX2	EPX	P11678	642
MRGPRX2	VIP	P01282	600
MRGPRX2	OGA	O60502	582
MRGPRX2	TACR1	P25103	571
MRGPRX2	TRPV1	Q8NER1	562
MRGPRX2	CMA1	P23946	544
MRGPRX2	NTS	P30990	511
MRGPRX2	KIT	P10721	511
MRGPRX2	CPA3	P15088	500
MRGPRX2	CPA4	Q9UI42	469

IntAct

11 interactions, top by confidence:

A	B	Type	Score
RAMP1	MRGPRX2	psi-mi:“MI:0915”(physical association)	0.400
MRGPRX2	RAMP2	psi-mi:“MI:0915”(physical association)	0.400
RAMP2	MRGPRX2	psi-mi:“MI:0915”(physical association)	0.400
RAMP3	MRGPRX2	psi-mi:“MI:0915”(physical association)	0.400
P		psi-mi:“MI:0914”(association)	0.350

BioGRID (1): MRGPRX2 (Affinity Capture-MS)

ESM2 similar proteins: Q2LL16, Q3KNA1, Q3UG50, Q3UG61, Q4QXU0, Q4QXU2, Q4QXU3, Q4QXU4, Q4QXU5, Q4QXU6, Q4QXX9, Q5U9D9, Q645T2, Q645T7, Q645V2, Q645V8, Q645Z2, Q646A2, Q646C4, Q646D6, Q646F4, Q646F6, Q67ES0, Q6L786, Q7TN39, Q7TN41, Q7TN44, Q7TN45, Q7TN49, Q7TN50, Q86SM5, Q8CIP3, Q8R4G1, Q8TDS7, Q91WW2, Q91WW3, Q91WW4, Q91WW5, Q91ZB5, Q91ZB9

Diamond homologs: B9VR26, O55197, O88680, P04201, P12526, P23749, P30554, P35410, Q16581, Q2LL16, Q3KNA1, Q3UG50, Q3UG61, Q4QXU0, Q4QXU2, Q4QXU3, Q4QXU4, Q4QXU5, Q4QXU6, Q4QXX9, Q5REI5, Q5U9D9, Q6L786, Q6TAC8, Q6XKD3, Q7TN38, Q7TN39, Q7TN40, Q7TN41, Q7TN44, Q7TN45, Q7TN49, Q7TN50, Q7TN51, Q86SM5, Q8CIP3, Q8NGA4, Q8R4G1, Q8TDS7, Q8VCJ6

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
CORT	up-regulates	MRGPRX2	binding
MRGPRX2	“up-regulates activity”	GNAS	binding
MRGPRX2	“up-regulates activity”	GNAL	binding
MRGPRX2	“up-regulates activity”	GNAI1	binding
MRGPRX2	“up-regulates activity”	GNAI3	binding
MRGPRX2	“up-regulates activity”	GNAO1	binding
MRGPRX2	“up-regulates activity”	GNAZ	binding
MRGPRX2	“up-regulates activity”	GNAQ	binding
MRGPRX2	“up-regulates activity”	GNA14	binding
Cortistatin14	“up-regulates activity”	MRGPRX2	“chemical activation”

Disease & clinical

Clinical variants and AI predictions

ClinVar

45 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	39
Likely benign	4
Benign	0

Top pathogenic / likely-pathogenic (0)

SpliceAI

225 predictions. Top by Δscore:

Variant	Effect	Δscore
11:19056426:CC:C	acceptor_gain	0.9900
11:19056427:CC:C	acceptor_gain	0.9900
11:19057711:A:AC	donor_gain	0.9900
11:19057712:C:CC	donor_gain	0.9900
11:19056425:CCC:C	acceptor_gain	0.9800
11:19056426:CCC:C	acceptor_gain	0.9800
11:19056428:C:CA	acceptor_loss	0.9800
11:19056428:C:CC	acceptor_gain	0.9800
11:19055908:C:A	donor_gain	0.9700
11:19056423:TGCCC:T	acceptor_gain	0.9600
11:19060620:TTAAC:T	donor_gain	0.9400
11:19057712:CT:C	donor_gain	0.9300
11:19060622:AACAC:A	donor_gain	0.9300
11:19060613:TCTTA:T	donor_loss	0.9200
11:19060614:CTTA:C	donor_loss	0.9200
11:19060615:TTACC:T	donor_loss	0.9200
11:19060616:TA:T	donor_loss	0.9200
11:19060617:AC:A	donor_loss	0.9200
11:19060618:C:CG	donor_loss	0.9200
11:19055907:T:TA	donor_gain	0.9100
11:19055554:GCCC:G	acceptor_gain	0.8900
11:19060612:CTCTT:C	donor_loss	0.8900
11:19056430:G:C	acceptor_loss	0.8800
11:19057716:T:C	donor_gain	0.8700
11:19056424:GCCC:G	acceptor_gain	0.8600
11:19056425:CCCC:C	acceptor_gain	0.8600
11:19056431:GAAA:G	acceptor_loss	0.8600
11:19055553:AGCC:A	acceptor_gain	0.8500
11:19056428:C:T	acceptor_gain	0.8400
11:19057707:C:A	donor_gain	0.8200

AlphaMissense

2145 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
11:19055707:G:C	F232L	0.969
11:19055707:G:T	F232L	0.969
11:19055709:A:G	F232L	0.969
11:19056040:G:C	S121R	0.960
11:19056040:G:T	S121R	0.960
11:19056042:T:G	S121R	0.960
11:19056049:G:C	S118R	0.955
11:19056049:G:T	S118R	0.955
11:19056051:T:G	S118R	0.955
11:19055797:A:C	S202R	0.940
11:19055797:A:T	S202R	0.940
11:19055799:T:G	S202R	0.940
11:19056193:G:C	S70R	0.936
11:19056193:G:T	S70R	0.936
11:19056195:T:G	S70R	0.936
11:19056031:G:C	S124R	0.931
11:19056031:G:T	S124R	0.931
11:19056033:T:G	S124R	0.931
11:19055584:A:C	S273R	0.927
11:19055584:A:T	S273R	0.927
11:19055586:T:G	S273R	0.927
11:19055920:G:C	S161R	0.901
11:19055920:G:T	S161R	0.901
11:19055922:T:G	S161R	0.901
11:19055943:A:G	W154R	0.901
11:19055943:A:T	W154R	0.901
11:19055671:G:C	F244L	0.894
11:19055671:G:T	F244L	0.894
11:19055673:A:G	F244L	0.894
11:19055587:G:C	S272R	0.875

dbSNP variants (sampled 300 via entrez): RS1001029716 (11:19054138 A>G), RS1001141253 (11:19060326 G>A), RS1001459842 (11:19058617 G>A), RS1001908808 (11:19061570 G>A,T), RS1002558738 (11:19057377 A>T), RS1003028557 (11:19057030 T>C), RS1003565979 (11:19058594 G>T), RS1003577212 (11:19054116 A>G), RS1003964883 (11:19061447 T>A), RS1004097550 (11:19061198 C>A,G), RS1005021001 (11:19056719 A>G), RS1005651940 (11:19057987 A>T), RS1005853504 (11:19056389 G>A), RS1005930556 (11:19058325 T>A), RS1006065700 (11:19061961 T>C)

Disease associations

OMIM: gene MIM:607228 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL5849 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

16 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 484,121 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL1200490	CETRORELIX	4	16,775
CHEMBL1457	HYDROCODONE	4	46,002
CHEMBL1738990	LEVOPROPOXYPHENE	4	654
CHEMBL2028850	ICATIBANT	4	108
CHEMBL485	CODEINE	4	73,486
CHEMBL52440	DEXTROMETHORPHAN	4	33,223
CHEMBL592	LEVORPHANOL	4	75,131
CHEMBL651	METHADONE	4	45,280
CHEMBL70	MORPHINE	4	128,573
CHEMBL248095	SINOMENINE	3	2,143
CHEMBL1254766	DEXTRORPHAN	2	6,521
CHEMBL1330	MORPHINE GLUCURONIDE	2	204
CHEMBL1908321	NORCODEINE	2	880
CHEMBL494480	ADL-5859	2	119
CHEMBL235363	SUBSTANCE P	1	55,007
CHEMBL4635331	HTL-0022562	1	15

PharmGKB: 1 entry (VIP=true, CPIC=false)

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: gpcr — Class A Orphans with emerging pharmacology

Most potent curated ligand interactions (10 total), top 10:

Ligand	Action	Affinity	Parameter
PAMP-12 (human)	Full agonist	7.68	pEC50
cortistatin-14	Full agonist	7.6	pEC50
compound 2 [PMID: 19230660]	Full agonist	6.5	pEC50
(R)-ZINC-3573	Agonist	6.12	pEC50
substance P	Agonist	5.97	pEC50
compound 48/80	Agonist	5.74	pEC50
TAN-67	Agonist	5.74	pEC50
GPR15L	Agonist	5.72	pEC50
ERAS-5024	Agonist	5.38	pEC50
SRIF-28	Agonist	5.38	pEC50

Binding affinities (BindingDB)

66 measured of 126 human assays (126 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
4-((S)-1-((R)-1-([1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-ylamino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide	IC50	3.7 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-((S)-4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(6,7-dihydro-[1,4]dioxino[2’,3’:4,5]benzo[1,2-d]thiazol-2-yl)propanamide	IC50	5.9 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-((R)-3-(5-((R)-1-amino-2,2,2-trifluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)propanamide	IC50	6 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
4-((R)-1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)-2-((S)-1,2-dihydroxyethyl)pyridine 1-oxide	IC50	7.8 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6,7-dihydro-[1,4]dioxino[2’,3’:4,5]benzo[1,2-d]thiazol-2-yl)propanamide	IC50	8.6 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-(4,4-difluoropiperidin-1-yl)-N-(6,7-dihydro-[1,4]dioxino[2’,3’:4,5]benzo[1,2-d]thiazol-2-yl)propanamide	IC50	10 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-N-(2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)-2-((R)-3-(5-((R)-1,2-dihydroxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)propanamide	IC50	11 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-((R)-4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)propanamide	IC50	14 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-((R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)propanamide	IC50	15 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
4-((R)-1-((S)-1-((6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)-2-(hydroxymethyl)pyridine 1-oxide	IC50	15 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-((S)-3-(5-((R)-1-amino-2,2-difluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)propanamide	IC50	17 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-N-([1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)-2-(4,4-difluoropiperidin-1-yl)propanamide	IC50	17 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
4-((S)-1-((S)-1-((6,7-dihydro-[1,4]dioxino[2’,3’:4,5]benzo[1,2-d]thiazol-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide	IC50	17 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-((S)-3-(5-((S)-1-amino-2,2-difluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)propanamide	IC50	18 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-((R)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)propanamide	IC50	18 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
4-((R)-1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)-2-(hydroxymethyl)pyridine 1-oxide	IC50	18 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-N-(2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)-2-((R)-3-(5-((S)-1,2-dihydroxyethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)propanamide	IC50	22 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-((S)-3-(5-((R)-1-amino-2,2,2-trifluoroethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)propanamide	IC50	24 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
4-((S)-1-((R)-1-((6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide	IC50	26 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-((S)-4,4-difluoro-3-(5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)propanamide	IC50	29 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
4-((S)-1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)-2-((S)-1,2-dihydroxyethyl)pyridine 1-oxide	IC50	30 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-((R)-4,4-difluoro-3-(5-(hydroxymethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)propanamide	IC50	30 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-((R)-4,4-difluoro-3-(1H-1,2,4-triazol-5-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)propanamide	IC50	31 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
4-((3S,4S)-1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl)-4-fluoropiperidin-3-yl)pyridine 1-oxide	IC50	32 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
2-(aminomethyl)-4-((R)-1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide	IC50	32 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(+)-Morphine	EC50	34 nM	US-10231963: Methods for treating depressive symptoms
4-((S)-1-((R)-1-((2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide	IC50	34 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-((R)-3-(5-(aminomethyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)propanamide	IC50	36 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-((S)-4,4-difluoro-3-(6-(hydroxymethyl)-5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)propanamide	IC50	36 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-((R)-4,4-difluoro-3-(5-((methylamino)methyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)propanamide	IC50	41 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-N-(2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)-2-((S)-2-(6-oxo-1,6-dihydropyridin-3-yl)morpholino)propanamide	IC50	49 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-((R)-4,4-difluoro-3-(5-(hydroxymethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)propanamide	IC50	49 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-((S)-4,4-difluoro-3-(6-(hydroxymethyl)-5-oxo-4,5-dihydropyrazin-2-yl)piperidin-1-yl)-N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)propanamide	IC50	58 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-(4,4-difluoropiperidin-1-yl)-N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)propanamide	IC50	85 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
4-((R)-1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)-2-((methylamino)methyl)pyridine 1-oxide formate	IC50	87 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-N-(2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)-2-((3R,5S)-3-fluoro-5-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide	IC50	90 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
4-((R)-4-((S)-1-((2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl)morpholin-2-yl)pyridine 1-oxide	IC50	93 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-N-(2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)-2-((R)-3-(5-((4,4-difluoropiperidin-1-yl)methyl)-6-oxo-1,6-dihydropyridin-3-yl)-4,4-difluoropiperidin-1-yl)propanamide	IC50	169 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-N-(2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)-2-((R)-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)propanamide	IC50	170 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-((R)-4,4-difluoro-3-(2-oxohexahydropyrimidin-5-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)propanamide	IC50	180 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
4-((S)-1-((S)-1-([1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-ylamino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide	IC50	196 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
4-((S)-1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4,5-b]thiazolo[4,5-e]pyridin-6-yl)amino)-1-oxopropan-2-yl)-4,4-difluoropiperidin-3-yl)pyridine 1-oxide	IC50	207 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
4-((R)-1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl)piperidin-3-yl)pyridine 1-oxide	IC50	222 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
4-((3R,4S)-1-((S)-1-((2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)amino)-1-oxopropan-2-yl)-4-fluoropiperidin-3-yl)pyridine 1-oxide	IC50	223 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-((R)-4,4-difluoro-3-(4-oxo-1,3,4,5-tetrahydrofuro[3,4-c]pyridin-7-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)propanamide	IC50	290 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-((S)-4,4-difluoro-3-(6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(6,7-dihydro-5H-indeno[5,6-d]thiazol-2-yl)propanamide	IC50	292 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-((R)-4,4-difluoro-3-(5-(morpholinomethyl)-6-oxo-1,6-dihydropyridin-3-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)propanamide	IC50	303 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-(4,4-difluoropiperidin-1-yl)-N-(thiazolo[4’,5’:4,5]benzo[1,2-d]oxazol-6-yl)propanamide	IC50	331 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-((S)-4,4-difluoro-3-(hydroxymethyl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)propanamide	IC50	438 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE
(S)-2-((S)-4,4-difluoro-3-(1H-1,2,4-triazol-5-yl)piperidin-1-yl)-N-(2,2-difluoro-[1,3]dioxolo[4’,5’:4,5]benzo[1,2-d]thiazol-6-yl)propanamide	IC50	509 nM	WO-2025064535: TRICYCLIC SUBSTITUTED AMINE COMPOUNDS, COMPOSITIONS AND METHODS OF USE

ChEMBL bioactivities

68 potent at pChembl≥5 of 109 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
10.00	IC50	0.1	nM	CHEMBL6176658
10.00	IC50	0.1	nM	CHEMBL6174680
10.00	IC50	0.1	nM	CHEMBL6161999
10.00	IC50	0.1	nM	CHEMBL6170821
10.00	IC50	0.1	nM	CHEMBL6172954
10.00	IC50	0.1	nM	CHEMBL6176922
8.60	IC50	2.512	nM	CHEMBL5184300
6.86	EC50	138	nM	CHEMBL5665416
6.84	EC50	144.5	nM	CHEMBL5192321
6.80	EC50	158.5	nM	CHEMBL503688
6.54	EC50	290	nM	CHEMBL5184932
6.54	EC50	288.4	nM	CHEMBL327745
6.54	EC50	290	nM	CHEMBL327745
6.50	EC50	316.2	nM	CHEMBL463274
6.42	EC50	380	nM	CHEMBL5665419
6.40	EC50	398.1	nM	CHEMBL502480
6.38	EC50	416.9	nM	CHEMBL5192321
6.37	EC50	426.6	nM	CHEMBL327745
6.30	EC50	501.2	nM	CORTISTATIN-14
6.21	EC50	616.6	nM	CETRORELIX
6.20	EC50	631	nM	CHEMBL502132
6.19	EC50	645.6	nM	CHEMBL5665379
6.16	EC50	691.8	nM	COMPLANADINE A
6.13	EC50	740	nM	(R)-ZINC-3573
6.13	EC50	740	nM	CHEMBL5665379
6.09	EC50	812.8	nM	CETRORELIX
6.05	EC50	900	nM	HTL-0022562
6.00	EC50	1000	nM	(R)-ZINC-3573
5.98	EC50	1047	nM	ANALOG OF DYNORPHIN A
5.97	EC50	1072	nM	SUBSTANCE P
5.96	EC50	1100	nM	ANALOG OF DYNORPHIN A
5.90	EC50	1259	nM	CHEMBL503202
5.79	EC50	1622	nM	CHEMBL5665430
5.74	EC50	1820	nM	CHEMBL5665379
5.70	EC50	1995	nM	CHEMBL505263
5.64	EC50	2291	nM	CHEMBL2028997
5.61	EC50	2450	nM	CHEMBL2028997
5.52	EC50	3000	nM	CHEMBL5665388
5.50	EC50	3162	nM	CHEMBL5665416
5.49	EC50	3236	nM	DEXTROMETHORPHAN
5.47	EC50	3388	nM	CHEMBL5665374
5.41	EC50	3890	nM	DEXTRORPHAN
5.40	EC50	3981	nM	SINOMENINE
5.38	EC50	4169	nM	DEXTRORPHAN
5.37	EC50	4266	nM	CHEMBL5665408
5.37	EC50	4300	nM	DEXTRORPHAN
5.30	EC50	5012	nM	CHEMBL5665374
5.29	EC50	5129	nM	ADL-5859
5.29	EC50	5129	nM	SUBSTANCE P
5.27	EC50	5370	nM	SINOMENINE

PubChem BioAssay actives

86 with measured affinity, of 519 total; 42 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
(2S)-2-[(3S)-4,4-difluoro-3-(1-oxidopyridin-1-ium-4-yl)piperidin-1-yl]-N-[5-(2,4-difluorophenoxy)pyrazin-2-yl]propanamide	1870716: Antagonist activity at human MRGPRX2 expressed in HEK293 cells co-expressing mouse Galpha15 assessed as inhibition of Cortistatin-14 induced Ca2+ mobilization preincubated for 30 mins followed by Cortistatin-14 addition by FLIPRtetra-calcium mobilization assay	ic50	0.0025	uM
(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]hexanoyl]amino]hexanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-N-[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-amino-5-carbamimidamido-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxohexan-2-yl]butanediamide	2161969: Agonist activity at N-terminal Flag-tagged human MRGPRX2 receptor expressed in tetracycline-induced FLP-IN/T-REX 293 cells assessed as increase in intracellular calcium release by FLIPR assay	ec50	0.1380	uM
(2S)-6-amino-2-[[(4R,7S,10S,13S,16S,19S,22S,25S,28S,31S,34S,37R)-19,34-bis(4-aminobutyl)-31-(2-amino-2-oxoethyl)-13,25,28-tribenzyl-16-[(1R)-1-hydroxyethyl]-7,10-bis(hydroxymethyl)-22-(1H-indol-3-ylmethyl)-6,9,12,15,18,21,24,27,30,33,36-undecaoxo-37-[[(2S)-pyrrolidine-2-carbonyl]amino]-1,2-dithia-5,8,11,14,17,20,23,26,29,32,35-undecazacyclooctatriacontane-4-carbonyl]amino]hexanoic acid	1802709: PRESTO-Tango Assay from Article 10.1038/nchembio.2334: “In silico design of novel probes for the atypical opioid receptor MRGPRX2.”	ec50	0.1400	uM
(7S)-2-(benzylamino)-N-methyl-N-(1-methylpiperidin-4-yl)-6-oxo-7-propan-2-yl-5,7-dihydrobenzimidazolo[1,2-d][1,4]benzodiazepine-11-carboxamide	414291: Agonist activity at human MrgX2 receptor	ec50	0.1585	uM
3-[(4aS,12aR)-2-methyl-1,3,4,5,12,12a-hexahydropyrido[3,4-b]acridin-4a-yl]phenol	2161969: Agonist activity at N-terminal Flag-tagged human MRGPRX2 receptor expressed in tetracycline-induced FLP-IN/T-REX 293 cells assessed as increase in intracellular calcium release by FLIPR assay	ec50	0.2884	uM
3-[(4aS,12aS)-2-methyl-1,3,4,5,12,12a-hexahydropyrido[3,4-b]acridin-4a-yl]phenol	1877601: Agonistic activity at MRGPRX2 (unknown origin)	ec50	0.2900	uM
3-[(4aR,12aS)-2-methyl-1,3,4,5,12,12a-hexahydropyrido[3,4-b]acridin-4a-yl]phenol	1802708: Intracellular Calcium Mobilization Assay from Article 10.1038/nchembio.2334: “In silico design of novel probes for the atypical opioid receptor MRGPRX2.”	ec50	0.2900	uM
(7S)-2-(cycloheptylamino)-11-(4-methyl-1,4-diazepane-1-carbonyl)-7-propan-2-yl-5,7-dihydrobenzimidazolo[1,2-d][1,4]benzodiazepin-6-one	414291: Agonist activity at human MrgX2 receptor	ec50	0.3162	uM
(4S,7S,10S,13S,16S,19S,22S,25S,28S,31S,34S,37S)-19,34-bis(4-aminobutyl)-31-(2-amino-2-oxoethyl)-37-[[2-[[(2S)-2-aminopropanoyl]amino]acetyl]amino]-13,25,28-tribenzyl-10,16-bis[(1R)-1-hydroxyethyl]-7-(hydroxymethyl)-22-(1H-indol-3-ylmethyl)-6,9,12,15,18,21,24,27,30,33,36-undecaoxo-1,2-dithia-5,8,11,14,17,20,23,26,29,32,35-undecazacyclooctatriacontane-4-carboxylic acid	2161969: Agonist activity at N-terminal Flag-tagged human MRGPRX2 receptor expressed in tetracycline-induced FLP-IN/T-REX 293 cells assessed as increase in intracellular calcium release by FLIPR assay	ec50	0.3800	uM
(7S)-2-(4-benzylpiperazin-1-yl)-N-methyl-N-(1-methylpiperidin-4-yl)-6-oxo-7-propan-2-yl-5,7-dihydrobenzimidazolo[1,2-d][1,4]benzodiazepine-11-carboxamide	414291: Agonist activity at human MrgX2 receptor	ec50	0.3981	uM
(2S)-6-amino-2-[[(4R,7S,10S,13R,16S,19R,22S,25S,28S,31S,34S,37R)-19,34-bis(4-aminobutyl)-31-(2-amino-2-oxoethyl)-13,25,28-tribenzyl-16-[(1R)-1-hydroxyethyl]-7,10-bis(hydroxymethyl)-22-(1H-indol-3-ylmethyl)-6,9,12,15,18,21,24,27,30,33,36-undecaoxo-37-[[(2S)-pyrrolidine-2-carbonyl]amino]-1,2-dithia-5,8,11,14,17,20,23,26,29,32,35-undecazacyclooctatriacontane-4-carbonyl]amino]hexanoic acid	414291: Agonist activity at human MrgX2 receptor	ec50	0.5012	uM
Cetrorelix	2161969: Agonist activity at N-terminal Flag-tagged human MRGPRX2 receptor expressed in tetracycline-induced FLP-IN/T-REX 293 cells assessed as increase in intracellular calcium release by FLIPR assay	ec50	0.6166	uM
(7S)-7-butan-2-yl-2-[3-(dimethylamino)propylamino]-6-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]-5,7-dihydrobenzimidazolo[1,2-d][1,4]benzodiazepine-11-carboxamide	414291: Agonist activity at human MrgX2 receptor	ec50	0.6310	uM
3-(2-methyl-1,3,4,5,12,12a-hexahydropyrido[3,4-b]acridin-4a-yl)phenol	2161969: Agonist activity at N-terminal Flag-tagged human MRGPRX2 receptor expressed in tetracycline-induced FLP-IN/T-REX 293 cells assessed as increase in intracellular calcium release by FLIPR assay	ec50	0.6456	uM
(1R,9S,10R,16R)-16-methyl-4-[(1R,9S,10R,16R)-16-methyl-6,14-diazatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-trien-5-yl]-6,14-diazatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-triene	2161972: Agonist activity at MRGPRX2 (unknown origin) expressed in HTLA cells assessed as induction of beta-arrestin 2 recruitment incubated for 18 to 24 hrs by PRESTO-Tango assay	ec50	0.6918	uM
(3R)-N,N-dimethyl-1-(5-phenylpyrazolo[1,5-a]pyrimidin-7-yl)pyrrolidin-3-amine	2161972: Agonist activity at MRGPRX2 (unknown origin) expressed in HTLA cells assessed as induction of beta-arrestin 2 recruitment incubated for 18 to 24 hrs by PRESTO-Tango assay	ec50	0.7400	uM
N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-[[(2S)-1-oxo-3-piperidin-4-yl-1-(4-pyridin-4-ylpiperazin-1-yl)propan-2-yl]amino]propan-2-yl]-2-oxospiro[1H-pyrido[2,3-d][1,3]oxazine-4,4’-piperidine]-1’-carboxamide	1652756: Agonist activity at MRGPX2 (unknown origin)	ec50	0.9000	uM
(2S)-6-amino-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-1-[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]hexanoic acid	1802708: Intracellular Calcium Mobilization Assay from Article 10.1038/nchembio.2334: “In silico design of novel probes for the atypical opioid receptor MRGPRX2.”	ec50	1.0000	uM
(2S)-2-[[(2S)-1-[(2S)-6-amino-2-[[(2S)-1-[(2S)-2-amino-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]pyrrolidine-2-carbonyl]amino]-N-[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-1-[[(2S)-1-amino-4-methylsulfanyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-2-oxoethyl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-1,5-dioxopentan-2-yl]pentanediamide	2161969: Agonist activity at N-terminal Flag-tagged human MRGPRX2 receptor expressed in tetracycline-induced FLP-IN/T-REX 293 cells assessed as increase in intracellular calcium release by FLIPR assay	ec50	1.0715	uM
(7S)-2-(3-acetamidopyrrolidin-1-yl)-7-butan-2-yl-6-oxo-N-[[3-(trifluoromethyl)phenyl]methyl]-5,7-dihydrobenzimidazolo[1,2-d][1,4]benzodiazepine-11-carboxamide	414291: Agonist activity at human MrgX2 receptor	ec50	1.2589	uM
7-methoxy-2-methyl-3,4,4a,8a-tetrahydro-1H-isoquinoline	2161969: Agonist activity at N-terminal Flag-tagged human MRGPRX2 receptor expressed in tetracycline-induced FLP-IN/T-REX 293 cells assessed as increase in intracellular calcium release by FLIPR assay	ec50	1.6218	uM
(7S)-7-butan-2-yl-6-oxo-2-(2-piperidin-1-ylethylamino)-N-[[3-(trifluoromethyl)phenyl]methyl]-5,7-dihydrobenzimidazolo[1,2-d][1,4]benzodiazepine-11-carboxamide	414291: Agonist activity at human MrgX2 receptor	ec50	1.9953	uM
(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-1-[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-3-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-carboxypropanoyl]amino]-4-oxobutanoyl]amino]pentanedioic acid	2161969: Agonist activity at N-terminal Flag-tagged human MRGPRX2 receptor expressed in tetracycline-induced FLP-IN/T-REX 293 cells assessed as increase in intracellular calcium release by FLIPR assay	ec50	2.2909	uM
5-amino-2-[[4-amino-2-[[2-[[2-[[6-amino-2-[[2-[[6-amino-2-[[1-[2-[[2-[[2-[[2-[[2-[[2-[[2-[[2-[[2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylpentanoyl]amino]-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]hexanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-3-carboxypropanoyl]amino]-4-oxobutanoyl]amino]-5-oxopentanoic acid	1802708: Intracellular Calcium Mobilization Assay from Article 10.1038/nchembio.2334: “In silico design of novel probes for the atypical opioid receptor MRGPRX2.”	ec50	2.3000	uM
N,N-dimethyl-1-(2-methyl-5-phenylpyrazolo[1,5-a]pyrimidin-7-yl)pyrrolidin-3-amine	2161972: Agonist activity at MRGPRX2 (unknown origin) expressed in HTLA cells assessed as induction of beta-arrestin 2 recruitment incubated for 18 to 24 hrs by PRESTO-Tango assay	ec50	3.0000	uM
(1R,9R,10S)-4-methoxy-17-methyl-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-triene	1802709: PRESTO-Tango Assay from Article 10.1038/nchembio.2334: “In silico design of novel probes for the atypical opioid receptor MRGPRX2.”	ec50	3.2000	uM
Dextromethorphan	2161972: Agonist activity at MRGPRX2 (unknown origin) expressed in HTLA cells assessed as induction of beta-arrestin 2 recruitment incubated for 18 to 24 hrs by PRESTO-Tango assay	ec50	3.2359	uM
(4S,4aS,7R,7aS,12bR)-3-methyl-2,4,4a,7,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinoline-7,9-diol	2161972: Agonist activity at MRGPRX2 (unknown origin) expressed in HTLA cells assessed as induction of beta-arrestin 2 recruitment incubated for 18 to 24 hrs by PRESTO-Tango assay	ec50	3.3884	uM
(1S,9S,10S)-17-methyl-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-trien-4-ol	2161969: Agonist activity at N-terminal Flag-tagged human MRGPRX2 receptor expressed in tetracycline-induced FLP-IN/T-REX 293 cells assessed as increase in intracellular calcium release by FLIPR assay	ec50	3.8904	uM
(1R,9R,10S)-17-methyl-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5-trien-4-ol	1802708: Intracellular Calcium Mobilization Assay from Article 10.1038/nchembio.2334: “In silico design of novel probes for the atypical opioid receptor MRGPRX2.”	ec50	3.9000	uM
(1R,9S,10S)-3-hydroxy-4,12-dimethoxy-17-methyl-17-azatetracyclo[7.5.3.01,10.02,7]heptadeca-2(7),3,5,11-tetraen-13-one	2161969: Agonist activity at N-terminal Flag-tagged human MRGPRX2 receptor expressed in tetracycline-induced FLP-IN/T-REX 293 cells assessed as increase in intracellular calcium release by FLIPR assay	ec50	3.9811	uM
(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]hexanoyl]amino]-3-(4-hydroxyphenyl)propanoic acid	2161969: Agonist activity at N-terminal Flag-tagged human MRGPRX2 receptor expressed in tetracycline-induced FLP-IN/T-REX 293 cells assessed as increase in intracellular calcium release by FLIPR assay	ec50	4.2658	uM
(2S)-6-amino-2-[[(2S)-1-[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]hexanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]pyrrolidine-2-carbonyl]amino]hexanoic acid	1802708: Intracellular Calcium Mobilization Assay from Article 10.1038/nchembio.2334: “In silico design of novel probes for the atypical opioid receptor MRGPRX2.”	ec50	4.3000	uM
N,N-diethyl-4-(5-hydroxyspiro[chromene-2,4’-piperidine]-4-yl)benzamide	1802709: PRESTO-Tango Assay from Article 10.1038/nchembio.2334: “In silico design of novel probes for the atypical opioid receptor MRGPRX2.”	ec50	5.1000	uM
(4S,4aS,7R,7aS,12bR)-9-methoxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-7-ol	2161972: Agonist activity at MRGPRX2 (unknown origin) expressed in HTLA cells assessed as induction of beta-arrestin 2 recruitment incubated for 18 to 24 hrs by PRESTO-Tango assay	ec50	5.4954	uM
Morphine	2161972: Agonist activity at MRGPRX2 (unknown origin) expressed in HTLA cells assessed as induction of beta-arrestin 2 recruitment incubated for 18 to 24 hrs by PRESTO-Tango assay	ec50	6.1659	uM
(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]hexanoyl]amino]-3-methylbutanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxybutanoic acid	2161969: Agonist activity at N-terminal Flag-tagged human MRGPRX2 receptor expressed in tetracycline-induced FLP-IN/T-REX 293 cells assessed as increase in intracellular calcium release by FLIPR assay	ec50	6.4565	uM
(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[2-[[2-[[(2S)-2-amino-3-(4-hydroxyphenyl)propanoyl]amino]acetyl]amino]acetyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-(diaminomethylideneamino)pentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]hexanoyl]amino]-3-methylbutanoyl]amino]-3-methylbutanoyl]amino]-3-hydroxybutanoic acid	1802708: Intracellular Calcium Mobilization Assay from Article 10.1038/nchembio.2334: “In silico design of novel probes for the atypical opioid receptor MRGPRX2.”	ec50	6.5000	uM
Codeine	2161972: Agonist activity at MRGPRX2 (unknown origin) expressed in HTLA cells assessed as induction of beta-arrestin 2 recruitment incubated for 18 to 24 hrs by PRESTO-Tango assay	ec50	6.7608	uM
(1S,9S,13S)-1,10,13-trimethyl-10-azatricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-4-ol	1802709: PRESTO-Tango Assay from Article 10.1038/nchembio.2334: “In silico design of novel probes for the atypical opioid receptor MRGPRX2.”	ec50	7.2000	uM
(1S,9S,13R)-1,10,13-trimethyl-10-azatricyclo[7.3.1.02,7]trideca-2(7),3,5-trien-4-ol	2161972: Agonist activity at MRGPRX2 (unknown origin) expressed in HTLA cells assessed as induction of beta-arrestin 2 recruitment incubated for 18 to 24 hrs by PRESTO-Tango assay	ec50	7.2444	uM
(4S)-5-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-5-amino-1-[[(2S)-6-amino-1-[[(2S)-5-carbamimidamido-1-[[(2S)-1-(carboxymethylamino)-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-1-oxopentan-2-yl]amino]-1-oxohexan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-4-methylsulfanyl-1-oxobutan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-[[(2S)-1-[(2S)-2-[[2-[[(2S)-2-amino-3-methylbutanoyl]amino]acetyl]amino]-5-carbamimidamidopentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoic acid	1802708: Intracellular Calcium Mobilization Assay from Article 10.1038/nchembio.2334: “In silico design of novel probes for the atypical opioid receptor MRGPRX2.”	ec50	8.9000	uM

CTD chemical–gene interactions

14 total (human), top 14 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Methotrexate	decreases expression, increases expression	2
sodium arsenite	increases expression	1
4-phenylenediamine	affects reaction, increases secretion, affects response to substance	1
alpha-curcumene	affects binding	1
CGP 52608	affects binding, increases reaction	1
Grape Seed Proanthocyanidins	increases expression, affects cotreatment	1
Nebivolol	affects binding	1
Benzo(a)pyrene	affects methylation, increases methylation	1
Catechin	affects cotreatment, increases expression	1
Colistin	affects reaction, increases secretion, increases response to substance	1
p-Methoxy-N-methylphenethylamine	affects response to substance	1
Dextromethorphan	affects response to substance, affects binding, affects reaction, increases secretion	1
Doxorubicin	decreases expression	1
Polymyxin B	affects reaction, increases secretion, increases response to substance	1

ChEMBL screening assays

52 unique, capped per target: 31 functional, 21 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL1015294	Functional	Agonist activity at human MrgX2 receptor	Discovery of non-peptidergic MrgX1 and MrgX2 receptor agonists and exploration of an initial SAR using solid-phase synthesis. — Bioorg Med Chem Lett
CHEMBL3721005	Binding	Activation of human MrgX2 receptor expressed in NIH/3T3 cells incubated for 5 days by beta-galactosidase reporter gene assay	Compounds for the treatment of pain and screening methods therefor

Cellosaurus cell lines

2 cell lines: 2 spontaneously immortalized cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_H465	CHO-K1/MRGPRX2	Spontaneously immortalized cell line	Female
CVCL_KY49	PathHunter CHO-K1 MRGPRX2 beta-arrestin	Spontaneously immortalized cell line	Female

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.