CALCRL

Summary

CALCRL (calcitonin receptor like receptor, HGNC:16709) is a protein-coding gene on chromosome 2q32.1, encoding Calcitonin gene-related peptide type 1 receptor (Q16602). G protein-coupled receptor which specificity is determined by its interaction with receptor-activity-modifying proteins (RAMPs).

Enables adrenomedullin binding activity; adrenomedullin receptor activity; and calcitonin gene-related peptide receptor activity. Involved in several processes, including G protein-coupled receptor signaling pathway; cellular response to sucrose stimulus; and receptor internalization. Located in several cellular components, including endoplasmic reticulum; endosome; and lysosome. Part of CGRP receptor complex and adrenomedullin receptor complex. Implicated in hereditary lymphedema.

Source: NCBI Gene 10203 — RefSeq curated summary.

At a glance

• Gene–disease (curated): lymphatic malformation 8 (Limited, GenCC)
• GWAS associations: 53
• Clinical variants (ClinVar): 53 total — 3 pathogenic
• Phenotypes (HPO): 7
• Druggable target: yes — 12 molecules with ChEMBL bioactivity
• MANE Select transcript: NM_005795

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:16709
Approved symbol	CALCRL
Name	calcitonin receptor like receptor
Location	2q32.1
Locus type	gene with protein product
Status	Approved
Aliases	CGRPR, CRLR
Ensembl gene	ENSG00000064989
Ensembl biotype	protein_coding
OMIM	114190
Entrez	10203

Gene structure

Transcript identifiers

Ensembl transcripts: 31 — 27 protein_coding, 3 protein_coding_CDS_not_defined, 1 retained_intron

ENST00000392370, ENST00000409998, ENST00000410068, ENST00000410102, ENST00000447403, ENST00000461244, ENST00000474212, ENST00000479784, ENST00000485973, ENST00000897822, ENST00000897823, ENST00000897824, ENST00000897825, ENST00000897826, ENST00000897827, ENST00000897828, ENST00000897829, ENST00000897830, ENST00000897831, ENST00000897832, ENST00000897833, ENST00000897834, ENST00000897835, ENST00000897836, ENST00000969621, ENST00000969622, ENST00000969623, ENST00000969624, ENST00000969625, ENST00000969626, ENST00000969627

RefSeq mRNA: 4 — MANE Select: NM_005795 NM_001271751, NM_001369434, NM_001369435, NM_005795

CCDS: CCDS2293

Canonical transcript exons

ENST00000392370 — 15 exons

Exon	Start	End
ENSE00000471484	187383173	187383305
ENSE00000471486	187380467	187380579
ENSE00000471488	187363376	187363502
ENSE00000471489	187360598	187360751
ENSE00000471493	187351920	187351961
ENSE00000783621	187352114	187352332
ENSE00000783622	187359063	187359129
ENSE00000783623	187359212	187359272
ENSE00000783626	187378940	187379031
ENSE00000783628	187380677	187380787
ENSE00001161377	187385545	187385631
ENSE00001366268	187387666	187387756
ENSE00001390679	187387329	187387493
ENSE00001585253	187448039	187448252
ENSE00003847958	187341964	187346399

Expression profiles

Bgee: expression breadth ubiquitous, 227 present calls, max score 96.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 22.8425 / max 2014.6905, expressed in 1192 samples.

FANTOM5 promoters (3 alternative TSS)

Promoter ID	TPM avg	Samples expressed
32796	16.9534	955
32797	5.4063	1052
32795	0.4827	212

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
right lung	UBERON:0002167	96.23	gold quality
upper lobe of left lung	UBERON:0008952	93.31	gold quality
upper lobe of lung	UBERON:0008948	93.28	gold quality
calcaneal tendon	UBERON:0003701	93.23	gold quality
lung	UBERON:0002048	92.77	gold quality
adrenal tissue	UBERON:0018303	91.80	gold quality
gall bladder	UBERON:0002110	91.71	gold quality
lower lobe of lung	UBERON:0008949	91.66	gold quality
right coronary artery	UBERON:0001625	91.63	gold quality
omental fat pad	UBERON:0010414	90.11	gold quality
peritoneum	UBERON:0002358	90.01	gold quality
adipose tissue of abdominal region	UBERON:0007808	89.40	gold quality
left coronary artery	UBERON:0001626	89.07	gold quality
tendon	UBERON:0000043	88.24	gold quality
smooth muscle tissue	UBERON:0001135	87.85	gold quality
coronary artery	UBERON:0001621	87.12	gold quality
subcutaneous adipose tissue	UBERON:0002190	87.06	gold quality
popliteal artery	UBERON:0002250	86.99	gold quality
tibial artery	UBERON:0007610	86.98	gold quality
right lobe of thyroid gland	UBERON:0001119	86.33	gold quality
visceral pleura	UBERON:0002401	85.71	gold quality
left lobe of thyroid gland	UBERON:0001120	85.57	gold quality
mucosa of stomach	UBERON:0001199	85.41	gold quality
thyroid gland	UBERON:0002046	85.36	gold quality
tendon of biceps brachii	UBERON:0008188	85.16	gold quality
adipose tissue	UBERON:0001013	84.87	gold quality
connective tissue	UBERON:0002384	84.39	gold quality
colonic epithelium	UBERON:0000397	84.31	gold quality
right atrium auricular region	UBERON:0006631	83.75	gold quality
aorta	UBERON:0000947	83.55	gold quality

Single-cell (SCXA)

Detected in 18 experiment(s), a significant marker in 17.

Experiment	Marker?	Max mean expression
E-HCAD-15	yes	2478.47
E-MTAB-8142	yes	872.98
E-GEOD-135922	yes	595.44
E-MTAB-10287	yes	65.40
E-HCAD-1	yes	54.06
E-HCAD-11	yes	40.83
E-GEOD-134144	yes	40.49
E-HCAD-10	yes	38.34
E-MTAB-6701	yes	32.59
E-MTAB-8410	yes	28.12
E-CURD-46	yes	27.60
E-HCAD-9	yes	16.61
E-MTAB-6678	yes	14.15
E-CURD-112	yes	7.95
E-MTAB-10553	yes	7.95

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): PROX1

miRNA regulators (miRDB)

225 targeting CALCRL, 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-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-656-3P	100.00	72.15	2788
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-126-5P	100.00	72.71	3180
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-188-3P	100.00	68.76	1240
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-3064-3P	100.00	70.09	1254
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-3692-3P	99.98	70.27	2139
HSA-MIR-4803	99.98	71.99	3117
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-LET-7F-2-3P	99.98	70.98	2588
HSA-MIR-1185-1-3P	99.98	71.04	2593
HSA-MIR-1185-2-3P	99.98	71.04	2593
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-485-3P	99.98	70.68	1585
HSA-MIR-539-3P	99.98	70.74	1616
HSA-MIR-548N	99.98	71.94	4170
HSA-MIR-568	99.98	69.86	2084
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955

Literature-anchored findings (GeneRIF, showing 40)

• Receptor activity modifying proteins interaction with human and porcine calcitonin receptor-like receptor (CRLR) in HEK-293 cells (PMID:11693189)
• This study aimed to identify the cellular location of calcitonin receptor-like receptor (CRLR) which is pharmacologically identical to CGRP receptor-1, a putative molecular target of CGRP and adrenomedullin (PMID:11814625)
• The CGRP receptor components, RAMP1 and CRLR, are down-regulated during myeloid differentiation of CD34+ cells, and CGRP receptor selectively promotes the development of CFU-GM. (PMID:11937264)
• results show the presence of calcitonin receptor-like receptor and receptor activity-modifying proteins in middle meningeal, middle cerebral, pial, and superficial temporal vessels (PMID:11973435)
• expression at the human implantation site (PMID:12213903)
• receptor activity-modifying protein 1 binds to the CRLR (PMID:12574158)
• Cysteine residues in the extracellular loops of hCRLR and in the extracellular domain of hRAMP2 thus appear to play distinct roles in the cell surface expression and function of the receptor heterodimer. (PMID:12630808)
• findings show that human skin keratinocytes and fibroblasts express adrenomedullin and its receptors L1-R and CRLR (PMID:12684703)
• CRLR gene promoter (PMID:12824306)
• Transcriptional regulation of the CRLR gene in microvascular endothelial cells by hypoxia. (PMID:12824306)
• TNF-alpha induced time- and dose-dependent decreases in the expression of CRLR mRNA in cultured human coronary artery smooth muscle cells, thereby diminishing AM-evoked cAMP production (PMID:15245870)
• Results demonstrated in the atria of heart failure patients there is an up-regulation of CGRP receptor by an increase of RAMP1 in association with CRLR. (PMID:15300632)
• novel function for RAMP3 in the post-endocytic sorting of the calcitonin receptor-like receptor. (PMID:15613468)
• The N-terminal domain of calcitonin receptor-like receptor is an autonomously folded unit possessing a well-defined structure and is significantly involved in ligand binding and specificity. (PMID:15641806)
• among women, the T allele of the SNP rs696574 (C –> T, in intron 6) was significantly more frequent in essential hypertension subjects (PMID:15797661)
• Structural and functional characteristics of the CGRP-receptor and of family B G-protein-coupled receptors in general. (PMID:16293613)
• the respective C-tails of hRAMP2 and -3 differentially affect hCRLR surface delivery and internalization (PMID:16410241)
• Endogenous CRLR is a key receptor for both adrenomedullin and CGRP in human endothelial cells. (PMID:16495482)
• Endogenous endothelial CRLR: subcellular localization, internalization and desensitization upon interaction with adrenomedullin and CGRP (PMID:16495482)
• adrenomedullin may prevent or reduce rheumatoid arthritis-fibroblast-like synoviocyte apoptosis, via up-regulation of its functional receptor CRLR/receptor activity-modifying protein-2 (PMID:16622024)
• Results will facilitate structural analysis of the recombinant protein will facilitate structural analysis of human RCP (receptor component protein), and allow further understanding of RCP function (PMID:17067815)
• CLR and RAMP1 traffic from endosomes to lysosomes by ubiquitin-independent mechanisms, where they are degraded at different rates (PMID:17310067)
• A mutated RAMP1 that cannot reach the cell surface, even in the presence of CRLR, indicating that the deficient targeting resulted from the altered conformation of the complex. (PMID:17503773)
• HRS mediates post-endocytic trafficking of protease-activated receptor 2 and calcitonin receptor-like receptor (PMID:17675298)
• Functional calcitonin gene-related peptide receptors are formed by the asymmetric assembly of a calcitonin receptor-like receptor homo-oligomer and a monomer of RAMP1. (PMID:17785463)
• There were some differences in mRNA expression for CL-R (higher) and RAMP3 (lower) in middle cerebral artery compared to coronary artery and pulmonary artery. (PMID:18198792)
• findings provided no significant linkage or association of adrenomedullin and CRLR-RAMP-2 genes with rheumatoid arthritis in the studied trio families (PMID:19210874)
• FACS analysis revealed the crucial CRLR regions (from TM1 to TM5) responsible for cell-surface translocation of receptor activity-modifying proteins. (PMID:19394311)
• Intrinsic cardiac adrenergic cells constitute a delta-opioid-regulated adrenopeptidergic paracrine system conferring robust cardioprotection through beta(2)-AR/CGRP-R co-signalling. (PMID:19581316)
• The study suggests a possible role of CALCRL in the pathogenesis of acute primary angle closure glaucoma (PACG) but not chronic PACG. (PMID:19898635)
• Activation of calcitonin receptor and calcitonin receptor-like receptor by membrane-anchored ligands. (PMID:19903822)
• Data describe the role of residues 23-60 of the calcitonin receptor-like receptor in binding with interaction sites within the N-terminus of the calcitonin gene-related peptide receptor. (PMID:19913063)
• the hCRLR C-tail is crucial for adrenomedullin-evoked cAMP production and internalization of the CRLR/RAMP2, while the receptor internalization is dependent on the aforementioned GPCR kinases, but not Gs coupling. (PMID:20074556)
• Structure-function analysis of helix 8 of human calcitonin receptor-like receptor within the adrenomedullin 1 receptor (PMID:20946927)
• Unexplained infertility was characterised by lower number of vessels stained with CRLR in endometrium compared to fertile controls. (PMID:20954838)
• Extracellular loops 1 and 3 and their associated transmembrane regions of the calcitonin receptor-like receptor are needed for CGRP receptor function. (PMID:21703310)
• The CRLR-RAMP2 interactions were confirmed for the full-length proteins on the cell surface by site-specific photo-crosslinking. (PMID:22102369)
• human CLR ECL3 is crucial for adrenomedullin (AM)-induced cAMP responses via three CLR/RAMP heterodimers, and activation of these heterodimers probably relies on AM-induced conformational changes (PMID:22142144)
• This study showed that CLR immunoreactivity was observed in satellite glial cells (SGCs) as well as in nerve fibers, but not in neurons. (PMID:22208649)
• CLR and RAMP1 co-localize in the enteric nervous system of the stomach, ileum and colon, and are in close proximity to their ligands CGRP and IMD (PMID:22484227)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	calcrlb	ENSDARG00000011571
mus_musculus	Calcrl	ENSMUSG00000059588
rattus_norvegicus	Calcrl	ENSRNOG00000054695

Paralogs (42): CALCR (ENSG00000004948), GIPR (ENSG00000010310), ADGRA2 (ENSG00000020181), GLP2R (ENSG00000065325), ADGRF5 (ENSG00000069122), ADGRL1 (ENSG00000072071), ADCYAP1R1 (ENSG00000078549), SCTR (ENSG00000080293), VIPR2 (ENSG00000106018), CRHR2 (ENSG00000106113), GHRHR (ENSG00000106128), ADGRD1 (ENSG00000111452), GLP1R (ENSG00000112164), ADGRG6 (ENSG00000112414), VIPR1 (ENSG00000114812), ADGRL2 (ENSG00000117114), CRHR1 (ENSG00000120088), ADGRB2 (ENSG00000121753), ADGRE5 (ENSG00000123146), ADGRE2 (ENSG00000127507), ADGRE3 (ENSG00000131355), ADGRB3 (ENSG00000135298), PTH2R (ENSG00000144407), ADGRG7 (ENSG00000144820), ADGRL3 (ENSG00000150471), ADGRA3 (ENSG00000152990), ADGRF1 (ENSG00000153292), ADGRF4 (ENSG00000153294), ADGRG4 (ENSG00000156920), ADGRG5 (ENSG00000159618), PTH1R (ENSG00000160801), ADGRL4 (ENSG00000162618), EVA1C (ENSG00000166979), ADGRF3 (ENSG00000173567), ADGRG2 (ENSG00000173698), ADGRE1 (ENSG00000174837), ADGRD2 (ENSG00000180264), ADGRB1 (ENSG00000181790), ADGRG3 (ENSG00000182885), ADGRA1 (ENSG00000197177)

Protein

Protein identifiers

Calcitonin gene-related peptide type 1 receptor — Q16602 (reviewed: Q16602)

Alternative names: Calcitonin receptor-like receptor

All UniProt accessions (3): Q16602, B8ZZJ4, E7EN01

UniProt curated annotations — full annotation on UniProt →

Function. G protein-coupled receptor which specificity is determined by its interaction with receptor-activity-modifying proteins (RAMPs). Together with RAMP1, form the receptor complex for calcitonin-gene-related peptides CALCA/CGRP1 and CALCB/CGRP2. Together with RAMP2 or RAMP3, function as receptor complexes for adrenomedullin (ADM and ADM2). Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-binding proteins (G proteins) and modulates the activity of downstream effectors. Activates cAMP-dependent pathway.

Subunit / interactions. Heterodimer of CALCRL and RAMP1; the receptor complex functions as CGRP receptor. Heterodimer of CALCRL and RAMP2 or CALCRL and RAMP3; the complexes function as adrenomedullin receptor.

Subcellular location. Cell membrane.

Tissue specificity. Predominantly expressed in the lung and heart.

Disease relevance. Lymphatic malformation 8 (LMPHM8) [MIM:618773] A form of primary lymphedema, a disease characterized by swelling of body parts due to developmental anomalies and functional defects of the lymphatic system. Adult patients with lymphedema may suffer from recurrent local infections. Impaired lymphatic drainage in the fetus can develop into hydrops fetalis, a severe condition characterized by excessive fluid accumulation in more than two fetal extra-vascular compartments and body cavities, placental enlargement and edema, pericardial or pleural effusion, or ascites. LMPHM8 is an autosomal recessive form characterized by onset in utero and fetal death due to non-immune hydrops fetalis. The disease may be caused by variants affecting the gene represented in this entry.

Similarity. Belongs to the G-protein coupled receptor 2 family.

RefSeq proteins (4): NP_001258680, NP_001356363, NP_001356364, NP_005786* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000832	GPCR_2_secretin-like	Family
IPR001879	GPCR_2_extracellular_dom	Domain
IPR003287	GPCR_2_calcitonin_rcpt_fam	Family
IPR003289	GPCR_2_CGRP1_rcpt	Family
IPR017981	GPCR_2-like_7TM	Domain
IPR017983	GPCR_2_secretin-like_CS	Conserved_site
IPR036445	GPCR_2_extracell_dom_sf	Homologous_superfamily
IPR050332	GPCR_2	Family

Pfam: PF00002, PF02793

UniProt features (74 total): helix 16, strand 10, turn 8, topological domain 7, transmembrane region 7, site 7, sequence variant 4, glycosylation site 3, disulfide bond 3, mutagenesis site 3, modified residue 2, signal peptide 1, chain 1, region of interest 1, sequence conflict 1

Structure

Experimental structures (PDB)

25 structures.

PDB	Method	Resolution (Å)
6ZHO	X-RAY DIFFRACTION	1.6
8AX7	X-RAY DIFFRACTION	1.65
6ZIS	X-RAY DIFFRACTION	1.73
4RWF	X-RAY DIFFRACTION	1.76
6V2E	X-RAY DIFFRACTION	1.83
7P0F	X-RAY DIFFRACTION	1.85
8AX6	X-RAY DIFFRACTION	1.9
6D1U	X-RAY DIFFRACTION	2.05
3N7S	X-RAY DIFFRACTION	2.1
6UVA	ELECTRON MICROSCOPY	2.3
7P0I	X-RAY DIFFRACTION	2.3
6UUS	ELECTRON MICROSCOPY	2.4
4RWG	X-RAY DIFFRACTION	2.44
3AQF	X-RAY DIFFRACTION	2.6
6UMG	X-RAY DIFFRACTION	2.7
8AX5	X-RAY DIFFRACTION	2.75
3N7P	X-RAY DIFFRACTION	2.8
5V6Y	X-RAY DIFFRACTION	2.8
3N7R	X-RAY DIFFRACTION	2.9
6UUN	ELECTRON MICROSCOPY	3
7KNT	ELECTRON MICROSCOPY	3.15
9MM5	ELECTRON MICROSCOPY	3.26
6E3Y	ELECTRON MICROSCOPY	3.3
7KNU	ELECTRON MICROSCOPY	3.49
9MNI	ELECTRON MICROSCOPY	4.06

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q16602-F1	79.03	0.41

Antibody-complex structures (SAbDab): 5 — 6E3Y, 6UMG, 6UUN, 6UUS, 6UVA

Functional residue map

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

Catalytic / active sites (7): 202 (required for adm interaction); 250 (required for ramp3 interaction); 286 (required for adm2 interaction); 288 (required for ramp2 interaction); 295 (required for adm2 interaction); 354 (required for adm2 interaction); 373 (required for adm interaction)

Post-translational modifications (2): 420, 445

Disulfide bonds (3): 48–74, 65–105, 88–127

Glycosylation sites (3): 66, 118, 123

Mutagenesis-validated functional residues (3):

Position	Phenotype
72	strongly reduced affinity for adrenomedullin.
92	strongly reduced affinity for adrenomedullin.
121	strongly reduced affinity for adrenomedullin.

Function

Pathways and Gene Ontology

Reactome pathways

11 pathways

ID	Pathway
R-HSA-418555	G alpha (s) signalling events
R-HSA-419812	Calcitonin-like ligand receptors
R-HSA-9856530	High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells
R-HSA-162582	Signal Transduction
R-HSA-372790	Signaling by GPCR
R-HSA-373080	Class B/2 (Secretin family receptors)
R-HSA-388396	GPCR downstream signalling
R-HSA-500792	GPCR ligand binding
R-HSA-8953897	Cellular responses to stimuli
R-HSA-9855142	Cellular responses to mechanical stimuli
R-HSA-9860931	Response of endothelial cells to shear stress

MSigDB gene sets: 338 (showing top): GSE45365_HEALTHY_VS_MCMV_INFECTION_CD8_TCELL_IFNAR_KO_UP, GSE45365_NK_CELL_VS_BCELL_DN, BEGUM_TARGETS_OF_PAX3_FOXO1_FUSION_UP, MODULE_64, GOBP_CELLULAR_RESPONSE_TO_CARBOHYDRATE_STIMULUS, GOBP_VESICLE_MEDIATED_TRANSPORT, GOBP_MUSCLE_CELL_PROLIFERATION, GOBP_CELLULAR_RESPONSE_TO_OXYGEN_CONTAINING_COMPOUND, GOBP_MONOATOMIC_CATION_TRANSPORT, VART_KSHV_INFECTION_ANGIOGENIC_MARKERS_UP, GOBP_ADENYLATE_CYCLASE_MODULATING_G_PROTEIN_COUPLED_RECEPTOR_SIGNALING_PATHWAY, GOBP_POSITIVE_REGULATION_OF_SMOOTH_MUSCLE_CELL_PROLIFERATION, JIANG_TIP30_TARGETS_UP, SHETH_LIVER_CANCER_VS_TXNIP_LOSS_PAM4, INGRAM_SHH_TARGETS_DN

GO Biological Process (18): angiogenesis (GO:0001525), calcium ion transport (GO:0006816), cell surface receptor signaling pathway (GO:0007166), G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger (GO:0007187), adenylate cyclase-activating G protein-coupled receptor signaling pathway (GO:0007189), heart development (GO:0007507), protein transport (GO:0015031), receptor internalization (GO:0031623), cellular response to sucrose stimulus (GO:0071329), positive regulation of vascular associated smooth muscle cell proliferation (GO:1904707), calcitonin gene-related peptide receptor signaling pathway (GO:1990408), adrenomedullin receptor signaling pathway (GO:1990410), vascular associated smooth muscle cell proliferation (GO:1990874), signal transduction (GO:0007165), G protein-coupled receptor signaling pathway (GO:0007186), cell population proliferation (GO:0008283), positive regulation of cell population proliferation (GO:0008284), smooth muscle cell proliferation (GO:0048659)

GO Molecular Function (7): adrenomedullin receptor activity (GO:0001605), calcitonin gene-related peptide receptor activity (GO:0001635), G protein-coupled receptor activity (GO:0004930), calcitonin receptor activity (GO:0004948), adrenomedullin binding (GO:1990409), transmembrane signaling receptor activity (GO:0004888), protein binding (GO:0005515)

GO Cellular Component (8): cytoplasm (GO:0005737), lysosome (GO:0005764), endosome (GO:0005768), endoplasmic reticulum (GO:0005783), plasma membrane (GO:0005886), adrenomedullin receptor complex (GO:1903143), CGRP receptor complex (GO:1990406), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-8 pathways:

Category	Pathways
Signaling by GPCR	2
GPCR downstream signalling	1
Class B/2 (Secretin family receptors)	1
Response of endothelial cells to shear stress	1
Signal Transduction	1
GPCR ligand binding	1
Cellular responses to stimuli	1
Cellular responses to mechanical stimuli	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
calcitonin family receptor activity	3
signal transduction	2
G protein-coupled receptor signaling pathway	2
calcitonin family receptor signaling pathway	2
cellular process	2
cellular anatomical structure	2
endomembrane system	2
calcitonin family receptor complex	2
blood vessel morphogenesis	1
anatomical structure formation involved in morphogenesis	1
metal ion transport	1
adenylate cyclase-modulating G protein-coupled receptor signaling pathway	1
adenylate cyclase activator activity	1
animal organ development	1
circulatory system development	1
transport	1
intracellular protein localization	1
establishment of protein localization	1
receptor-mediated endocytosis	1
response to sucrose	1
cellular response to disaccharide stimulus	1
positive regulation of smooth muscle cell proliferation	1
regulation of vascular associated smooth muscle cell proliferation	1
vascular associated smooth muscle cell proliferation	1
smooth muscle cell proliferation	1
cell communication	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
G protein-coupled receptor activity	1
cell population proliferation	1
regulation of cell population proliferation	1
positive regulation of cellular process	1
muscle cell proliferation	1
transmembrane signaling receptor activity	1
calcitonin binding	1
calcitonin family binding	1
signaling receptor activity	1
binding	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1122 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
CALCRL	RAMP3	O60896	999
CALCRL	RAMP2	O60895	999
CALCRL	RAMP1	O60894	999
CALCRL	ADM	P35318	999
CALCRL	ADM2	Q7Z4H4	985
CALCRL	CRCP	O75575	980
CALCRL	CALCB	P10092	957
CALCRL	IAPP	P10997	937
CALCRL	CALCA	P01258	932
CALCRL	TAC1	P20366	658
CALCRL	ARRB1	P49407	587
CALCRL	VIP	P01282	575
CALCRL	TACR1	P25103	529
CALCRL	ACKR5	O15218	507
CALCRL	EDN1	P05305	496

IntAct

32 interactions, top by confidence:

A	B	Type	Score
CALCRL	RAMP1	psi-mi:“MI:0407”(direct interaction)	0.810
RAMP1	CALCRL	psi-mi:“MI:0407”(direct interaction)	0.810
RAMP1	CALCRL	psi-mi:“MI:0915”(physical association)	0.810
CALCRL	RAMP1	psi-mi:“MI:0915”(physical association)	0.810
CALCRL	RAMP1	psi-mi:“MI:2364”(proximity)	0.810
CALCRL	RAMP1	psi-mi:“MI:0403”(colocalization)	0.810
RAMP2	CALCRL	psi-mi:“MI:0915”(physical association)	0.760
CALCRL	RAMP2	psi-mi:“MI:0915”(physical association)	0.760
RAMP2	CALCRL	psi-mi:“MI:2364”(proximity)	0.760
RAMP2	CALCRL	psi-mi:“MI:0407”(direct interaction)	0.760
CALCRL	RAMP2	psi-mi:“MI:0407”(direct interaction)	0.760
CALCRL	CALCA	psi-mi:“MI:0915”(physical association)	0.710
CALCA	RAMP1	psi-mi:“MI:0915”(physical association)	0.610
RAMP3	CALCRL	psi-mi:“MI:0915”(physical association)	0.470
CALCRL	RAMP3	psi-mi:“MI:2364”(proximity)	0.470
CALCRL	RAMP3	psi-mi:“MI:0915”(physical association)	0.470
ADM	CALCRL	psi-mi:“MI:0407”(direct interaction)	0.440
CALCRL	CALCA	psi-mi:“MI:0915”(physical association)	0.400

BioGRID (14): CALCRL (Affinity Capture-Luminescence), CALCRL (Reconstituted Complex), RAMP1 (Reconstituted Complex), RAMP1 (Reconstituted Complex), Ramp1 (Reconstituted Complex), RAMP1 (Affinity Capture-Western), RAMP3 (Reconstituted Complex), RAMP1 (Reconstituted Complex), RAMP1 (Co-localization), RAMP1 (Affinity Capture-Western), CALCRL (Affinity Capture-Western), RAMP1 (Affinity Capture-Western), CRCP (Affinity Capture-Western), CALCA (Co-purification)

ESM2 similar proteins: A6QP74, O08893, O35659, O97148, P23811, P25107, P25117, P30082, P30083, P30988, P32214, P32215, P32241, P32301, P35000, P35464, P41586, P41587, P41588, P43220, P49190, P70205, P70555, P79222, P83120, Q09460, Q0P4Y4, Q16602, Q28992, Q29627, Q5FWI2, Q60755, Q63118, Q68EK2, Q7ZXS8, Q8AXU4, Q8WN93, Q90308, Q91085, Q91V95

Diamond homologs: A0A2Z2U4G9, A6QP74, O35659, O42602, O42603, O46502, O62772, O95838, P23811, P25107, P25117, P25961, P30082, P30083, P32082, P32215, P32241, P32301, P34998, P34999, P35000, P35347, P35353, P41586, P41587, P41588, P41593, P43218, P43219, P43220, P47866, P47871, P47872, P48546, P48960, P49190, P50133, P70205, P70555, P97751

SIGNOR signaling

2 interactions.

A	Effect	B	Mechanism
CALCRL	“form complex”	“Adrenomedullin receptor AM1 complex”	binding
CALCRL	“form complex”	“Adrenomedullin receptor AM2 complex”	binding

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	3
Likely pathogenic	0
Uncertain significance	34
Likely benign	4
Benign	4

Top pathogenic / likely-pathogenic (3)

Variant ID	HGVS	Classification
148022	GRCh38/hg38 2q31.3-32.1(chr2:180942902-187372388)x1	Pathogenic
635896	Single allele	Pathogenic
812514	NM_005795.6(CALCRL):c.611TAG[1] (p.Val205del)	Pathogenic

SpliceAI

1907 predictions. Top by Δscore:

Variant	Effect	Δscore
2:187352108:CCATA:C	donor_loss	1.0000
2:187352110:ATAC:A	donor_loss	1.0000
2:187352111:TA:T	donor_loss	1.0000
2:187352154:T:TA	donor_gain	1.0000
2:187352299:CGCG:C	acceptor_gain	1.0000
2:187352302:G:C	acceptor_gain	1.0000
2:187359127:CAA:C	acceptor_gain	1.0000
2:187359130:C:CC	acceptor_gain	1.0000
2:187359210:A:AC	donor_gain	1.0000
2:187359211:C:CC	donor_gain	1.0000
2:187359211:CTTGT:C	donor_gain	1.0000
2:187359271:TC:T	acceptor_gain	1.0000
2:187359272:CC:C	acceptor_gain	1.0000
2:187359273:C:CC	acceptor_gain	1.0000
2:187360617:C:CT	donor_gain	1.0000
2:187360747:CTAAC:C	acceptor_gain	1.0000
2:187360748:TAAC:T	acceptor_gain	1.0000
2:187360751:CCTG:C	acceptor_loss	1.0000
2:187360753:T:A	acceptor_loss	1.0000
2:187363374:A:AC	donor_gain	1.0000
2:187363375:C:CC	donor_gain	1.0000
2:187363375:CAGG:C	donor_gain	1.0000
2:187363501:TCC:T	acceptor_loss	1.0000
2:187363504:T:A	acceptor_loss	1.0000
2:187379032:C:CC	acceptor_gain	1.0000
2:187379039:T:C	acceptor_gain	1.0000
2:187379039:T:TC	acceptor_gain	1.0000
2:187379041:G:GC	acceptor_gain	1.0000
2:187380462:CATA:C	donor_loss	1.0000
2:187380463:ATAC:A	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000032197 (2:187381496 C>T), RS1000036915 (2:187372005 T>C), RS1000089119 (2:187419210 A>G), RS1000131087 (2:187421452 C>G), RS1000141803 (2:187374354 T>A), RS1000156592 (2:187420716 T>C,G), RS1000167767 (2:187393338 T>A), RS1000187014 (2:187441001 T>G), RS1000222543 (2:187347364 G>A), RS1000257711 (2:187447786 T>C), RS1000284025 (2:187428728 C>A,T), RS1000294368 (2:187378840 A>G,T), RS1000341717 (2:187433796 T>C), RS1000358547 (2:187385983 G>T), RS1000384611 (2:187441179 T>C)

Disease associations

OMIM: gene MIM:114190 | disease phenotypes: MIM:618773

GenCC curated gene-disease

Disease	Classification	Inheritance
lymphatic malformation 8	Limited	Unknown

Mondo (2): lymphatic malformation 8 (MONDO:0032907), neurodevelopmental disorder (MONDO:0700092)

Orphanet (0):

HPO phenotypes

7 total (7 of 7 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0001561	Polyhydramnios
HP:0001698	Pericardial effusion
HP:0001790	Nonimmune hydrops fetalis
HP:0002202	Pleural effusion
HP:0003826	Stillbirth
HP:0007430	Generalized edema

GWAS associations

53 associations (top):

Study	Trait	p-value
GCST002782_236	Waist-to-hip ratio adjusted for body mass index	7.000000e-07
GCST002782_237	Waist-to-hip ratio adjusted for body mass index	6.000000e-10
GCST002782_238	Waist-to-hip ratio adjusted for body mass index	2.000000e-06
GCST002782_239	Waist-to-hip ratio adjusted for body mass index	3.000000e-10
GCST002783_53	Body mass index	8.000000e-06
GCST003818_76	Resting heart rate	6.000000e-16
GCST004064_33	Waist-hip ratio	7.000000e-07
GCST004064_39	Waist-hip ratio	1.000000e-12
GCST004064_44	Waist-hip ratio	7.000000e-08
GCST004505_20	Waist-to-hip ratio adjusted for BMI (adjusted for smoking behaviour)	2.000000e-08
GCST004567_139	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	1.000000e-11
GCST004567_40	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	3.000000e-08
GCST004567_61	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	3.000000e-08
GCST004567_70	Waist-to-hip ratio adjusted for BMI (joint analysis for main effect and physical activity interaction)	1.000000e-11
GCST004576_79	Waist-to-hip ratio adjusted for body mass index	5.000000e-10
GCST004576_80	Waist-to-hip ratio adjusted for body mass index	2.000000e-08
GCST004576_81	Waist-to-hip ratio adjusted for body mass index	3.000000e-06
GCST004576_82	Waist-to-hip ratio adjusted for body mass index	2.000000e-12
GCST004576_83	Waist-to-hip ratio adjusted for body mass index	7.000000e-12
GCST004578_107	Waist-to-hip ratio adjusted for BMI in active individuals	3.000000e-06
GCST004578_116	Waist-to-hip ratio adjusted for BMI in active individuals	8.000000e-10
GCST004578_16	Waist-to-hip ratio adjusted for BMI in active individuals	3.000000e-06
GCST004578_72	Waist-to-hip ratio adjusted for BMI in active individuals	8.000000e-10
GCST004578_90	Waist-to-hip ratio adjusted for BMI in active individuals	3.000000e-06
GCST005194_136	Coronary artery disease	2.000000e-06
GCST006979_49	Heel bone mineral density	4.000000e-10
GCST008058_218	Estimated glomerular filtration rate	2.000000e-12
GCST008059_247	Estimated glomerular filtration rate	2.000000e-10
GCST010146_8	Serum immune biomarker levels	9.000000e-10
GCST010698_54	Subcortical volume (min-P)	3.000000e-10

EFO canonical traits (15, from GWAS)

EFO ID	Trait name
EFO:0007788	BMI-adjusted waist-hip ratio
EFO:0004340	body mass index
EFO:0004343	waist-hip ratio
EFO:0004318	smoking behavior
EFO:0008002	physical activity measurement
EFO:0009270	heel bone mineral density
EFO:0004869	YKL40 measurement
EFO:0004872	inflammatory biomarker measurement
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0005665	white matter hyperintensity measurement
EFO:0009819	comparative body size at age 10, self-reported
EFO:0008039	BMI-adjusted hip circumference
EFO:0004736	aspartate aminotransferase measurement
EFO:0007789	BMI-adjusted waist circumference

MeSH disease descriptors (1)

Descriptor	Name	Tree numbers
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (4): CHEMBL2107838 (PROTEIN COMPLEX), CHEMBL2109232 (PROTEIN COMPLEX), CHEMBL2111191 (PROTEIN COMPLEX), CHEMBL3798 (SINGLE PROTEIN)

Molecules with ChEMBL bioactivity

12 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 3,782 (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
CHEMBL2103758	PRAMLINTIDE	4	883
CHEMBL2364638	UBROGEPANT	4	428
CHEMBL3989767	CALCITONIN SALMON	4	666
CHEMBL3991065	ATOGEPANT	4	251
CHEMBL2178422	RIMEGEPANT	4	417
CHEMBL2397415	ZAVEGEPANT	4	296
CHEMBL236593	TELCAGEPANT	3	254
CHEMBL4802169	CAGRILINTIDE	3
CHEMBL1910936	MK3207	2	163
CHEMBL207197	OLCEGEPANT	2	347
CHEMBL3334624	BI-44370	2	62
CHEMBL4635331	HTL-0022562	1	15

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs6710852	CALCRL		0.00	0

GtoPdb / IUPHAR curated pharmacology

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

Target class: gpcr — Calcitonin receptors

Binding affinities (BindingDB)

65 measured of 68 human assays (68 total across all organisms); most potent 50 below. Values come from heterogeneous assays and are not directly comparable.

Ligand	Measure	Value	Patent
Atogepant	KI	0.015 nM	US-10272077: Piperidinone carboxamide azaindane CGRP receptor antagonists
(3S)-N-[(3S,5S,6R)-6-methyl-2-oxo-1-(2,2,2-trifluoroethyl)-5-(2,3,5-trifluorophenyl)piperidin-3-yl]-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[b]pyridine]-3’-carboxamide	KI	0.017 nM	US-10272077: Piperidinone carboxamide azaindane CGRP receptor antagonists
N-[(1R)-1-(3,5-difluorophenyl)ethyl]-3-fluoro-2,2-dimethyl-N-[(E)-3-[(3S)-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[b]pyridine]-3’-yl]prop-2-enyl]propanamide	KI	0.041 nM	US-8552023: Non-amidic linkers with branched termini as CGRP receptor antagonists
N-[(1R)-1-(3,5-difluorophenyl)ethyl]-N-[(E)-3-[(3S)-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[b]pyridine]-3’-yl]prop-2-enyl]-1-(trifluoromethyl)cyclopropane-1-carboxamide	KI	0.05 nM	US-8552023: Non-amidic linkers with branched termini as CGRP receptor antagonists
(3S)-N-[(3S,5S)-1-(cyclobutylmethyl)-5-(2,3-difluorophenyl)-2-oxopiperidin-3-yl]-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[b]pyridine]-3’-carboxamide	KI	0.055 nM	US-9833448: Piperidinone carboxamide azaindane CGRP receptor antagonists
(3S)-N-[(3S,5S,6R)-1-(cyclobutylmethyl)-5-(2,3-difluorophenyl)-6-methyl-2-oxopiperidin-3-yl]-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[b]pyridine]-3’-carboxamide	KI	0.055 nM	US-10272077: Piperidinone carboxamide azaindane CGRP receptor antagonists
1’-[[(3S)-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,7’-6,8-dihydrocyclopenta[g]quinoline]-3’-yl]methyl]-3’-propan-2-ylspiro[2,3-dihydro-1H-naphthalene-4,5’-imidazolidine]-2’,4’-dione	KI	0.057 nM	US-8507477: 3- and 6-quinolines with N-attached heterocyclic CGRP receptor antagonists
(3S)-3’-[[(8R)-8-(3,5-difluorophenyl)-6,8-dimethyl-10-oxo-6,9-diazaspiro[4.5]decan-9-yl]methyl]spiro[1H-pyrrolo[2,3-b]pyridine-3,7’-6,8-dihydrocyclopenta[g]quinoline]-2-one	KI	0.062 nM	US-8507477: 3- and 6-quinolines with N-attached heterocyclic CGRP receptor antagonists
3-chloro-N-[(1R)-1-(3,5-difluorophenyl)ethyl]-2,2-dimethyl-N-[(E)-3-[(3S)-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[b]pyridine]-3’-yl]prop-2-enyl]propanamide	KI	0.065 nM	US-8552023: Non-amidic linkers with branched termini as CGRP receptor antagonists
Ubrogepant	KI	0.067 nM	US-10272077: Piperidinone carboxamide azaindane CGRP receptor antagonists
(3S)-N-[(3S,5S,6R)-6-methyl-5-(2-methylphenyl)-2-oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl]-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[b]pyridine]-3’-carboxamide	KI	0.067 nM	US-10272077: Piperidinone carboxamide azaindane CGRP receptor antagonists
(3S)-N-[(3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-[[1-(trifluoromethyl)cyclopropyl]methyl]piperidin-3-yl]-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[b]pyridine]-3’-carboxamide	KI	0.093 nM	US-10272077: Piperidinone carboxamide azaindane CGRP receptor antagonists
N-[(1R)-1-(3-fluoro-4-methylphenyl)ethyl]-2,2-dimethyl-N-[(E)-3-[(3S)-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[b]pyridine]-3’-yl]prop-2-enyl]propanamide	KI	0.13 nM	US-8552023: Non-amidic linkers with branched termini as CGRP receptor antagonists
(3S)-3’-[[(8R)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]decan-9-yl]methyl]spiro[1H-pyrrolo[2,3-b]pyridine-3,7’-6,8-dihydrocyclopenta[g]quinoline]-2-one	KI	0.14 nM	US-8507477: 3- and 6-quinolines with N-attached heterocyclic CGRP receptor antagonists
(3S)-5-cyano-N-[(3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl]-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[b]pyridine]-3’-carboxamide	KI	0.14 nM	US-10272077: Piperidinone carboxamide azaindane CGRP receptor antagonists
(6S)-N-[(3S,5S,6R)-6-methyl-2-oxo-5-phenyl-1-(2,2,2-trifluoroethyl)piperidin-3-yl]-6’-oxospiro[5,7-dihydrocyclopenta[b]pyridine-6,5’-7H-pyrrolo[2,3-d]pyrimidine]-3-carboxamide	KI	0.17 nM	US-10272077: Piperidinone carboxamide azaindane CGRP receptor antagonists
2-[(8R)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]decan-9-yl]-N-(5’-oxo-2’-phenylspiro[1,3-dihydroindene-2,4’-1H-imidazole]-5-yl)acetamide	KI	0.21 nM	US-8569291: Bicyclic dihydroimidazolone CGRP receptor antagonists
(3S)-N-[(3S,5S)-5-(2-fluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl]-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[b]pyridine]-3’-carboxamide	KI	0.21 nM	US-10272077: Piperidinone carboxamide azaindane CGRP receptor antagonists
[1-(7-cyclohexyl-6,8-dihydro-5H-imidazo[1,5-a]pyrazin-3-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl] 4-(2-oxo-1H-quinolin-3-yl)piperidine-1-carboxylate	IC50	0.22 nM	US-9695176: Substituted imidazo[1,5-a]pyrazines as CGRP receptor antagonists
(3S)-N-[(3S,5S)-5-(2-chloro-6-fluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)piperidin-3-yl]-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[b]pyridine]-3’-carboxamide	KI	0.25 nM	US-10272077: Piperidinone carboxamide azaindane CGRP receptor antagonists
[1-(7-benzyl-6,8-dihydro-5H-imidazo[1,5-a]pyrazin-3-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl] 4-(2-oxo-1H-quinolin-3-yl)piperidine-1-carboxylate	IC50	0.26 nM	US-9695176: Substituted imidazo[1,5-a]pyrazines as CGRP receptor antagonists
5-methyl-1-[[(3S)-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,7’-6,8-dihydrocyclopenta[g]quinoline]-3’-yl]methyl]-5-phenyl-3-propan-2-ylimidazolidine-2,4-dione	KI	0.28 nM	US-8507477: 3- and 6-quinolines with N-attached heterocyclic CGRP receptor antagonists
1-[[(3S)-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,7’-6,8-dihydrocyclopenta[g]quinoline]-3’-yl]methyl]-3-propan-2-yl-1,3-diazaspiro[4.6]undecane-2,4-dione	KI	0.34 nM	US-8507477: 3- and 6-quinolines with N-attached heterocyclic CGRP receptor antagonists
N-[(1R)-1-(3,5-difluorophenyl)ethyl]-2,2-dimethyl-N-[(E)-3-[(2S)-1’-methyl-2’,4’-dioxospiro[1,3-dihydroindene-2,5’-imidazolidine]-5-yl]prop-2-enyl]propanamide	KI	0.43 nM	US-8552023: Non-amidic linkers with branched termini as CGRP receptor antagonists
(3S)-3’-[[(9S)-9-(3,5-difluorophenyl)-11-oxo-6,10-diazaspiro[4.6]undecan-10-yl]methyl]spiro[1H-pyrrolo[2,3-b]pyridine-3,7’-6,8-dihydrocyclopenta[g]quinoline]-2-one	KI	0.49 nM	US-8507477: 3- and 6-quinolines with N-attached heterocyclic CGRP receptor antagonists
(3S)-3’-[[(8S)-8-(3,5-difluorophenyl)-6-oxo-7-azaspiro[4.5]decan-7-yl]methyl]spiro[1H-pyrrolo[2,3-b]pyridine-3,7’-6,8-dihydrocyclopenta[g]quinoline]-2-one	KI	0.77 nM	US-8507477: 3- and 6-quinolines with N-attached heterocyclic CGRP receptor antagonists
(2S)-7-[[(9S)-9-(3,5-difluorophenyl)-11-oxo-6,10-diazaspiro[4.6]undecan-10-yl]methyl]spiro[1,3-dihydrocyclopenta[b]quinoline-2,3’-1H-pyrrolo[2,3-b]pyridine]-2’-one	KI	0.89 nM	US-8507477: 3- and 6-quinolines with N-attached heterocyclic CGRP receptor antagonists
(3S)-N-[(5S,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl]-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[b]pyridine]-3’-carboxamide	IC50	0.93 nM	US-9227973: Pyridine CGRP receptor antagonists
(3S)-3’-[[2-(2-chlorophenyl)-4-oxo-1,3-diazaspiro[4.4]non-1-en-3-yl]methyl]spiro[1H-pyrrolo[2,3-b]pyridine-3,7’-6,8-dihydrocyclopenta[g]quinoline]-2-one	KI	1.3 nM	US-8507477: 3- and 6-quinolines with N-attached heterocyclic CGRP receptor antagonists
2-[(8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]decan-9-yl]-N-(5’-oxo-2’-phenylspiro[1,3-dihydroindene-2,4’-1H-imidazole]-5-yl)acetamide	KI	1.6 nM	US-8569291: Bicyclic dihydroimidazolone CGRP receptor antagonists
N-[(3R,6S)-6-(2,3-difluorophenyl)-1-(2-hydroxy-2-methylpropyl)-2-oxoazepan-3-yl]-2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-carboxamide	KI	1.7 nM	US-10272077: Piperidinone carboxamide azaindane CGRP receptor antagonists
[1-(7-ethyl-6,8-dihydro-5H-imidazo[1,5-a]pyrazin-3-yl)-2-(7-methyl-1H-indazol-5-yl)ethyl] 4-(2-oxo-1H-quinolin-3-yl)piperidine-1-carboxylate	IC50	1.7 nM	US-9695176: Substituted imidazo[1,5-a]pyrazines as CGRP receptor antagonists
N-[(3R,6S)-6-(2,3-difluorophenyl)-2-oxo-1-(2,2,2-trifluoroethyl)azepan-3-yl]-2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-carboxamide	KI	1.9 nM	US-10272077: Piperidinone carboxamide azaindane CGRP receptor antagonists
[2-(7-methyl-1H-indazol-5-yl)-1-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)ethyl] 4-(2-oxo-1H-quinolin-3-yl)piperidine-1-carboxylate	IC50	2.95 nM	US-9695176: Substituted imidazo[1,5-a]pyrazines as CGRP receptor antagonists
N-[(6S,9R)-6-(2,3-difluorophenyl)-3-(2-hydroxypropan-2-yl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[c]pyridine]-3’-carboxamide	KI	4.3 nM	US-10272077: Piperidinone carboxamide azaindane CGRP receptor antagonists
(3S)-N-[(6R,9R)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl]-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[b]pyridine]-3’-carboxamide	IC50	4.5 nM	US-9227973: Pyridine CGRP receptor antagonists
(3S)-N-[(5R,6S,9R)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl]-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[b]pyridine]-3’-carboxamide	IC50	6.3 nM	US-9227973: Pyridine CGRP receptor antagonists
N-[(3R,6S)-6-(2,3-difluorophenyl)-1-methyl-2-oxoazepan-3-yl]-2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-carboxamide	KI	7.4 nM	US-10272077: Piperidinone carboxamide azaindane CGRP receptor antagonists
(3S)-2-oxo-N-(6-phenyl-5,6,7,8-tetrahydroquinolin-8-yl)spiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[b]pyridine]-3’-carboxamide	IC50	22 nM	US-9227973: Pyridine CGRP receptor antagonists
(3S)-N-[(5R,6S,9R)-6-(2,3-difluorophenyl)-5-fluoro-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl]-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[b]pyridine]-3’-carboxamide	IC50	22 nM	US-9227973: Pyridine CGRP receptor antagonists
N-(5’-oxo-2’-phenylspiro[1,3-dihydroindene-2,4’-1H-imidazole]-5-yl)-2-[2-oxo-3-(1,3-thiazol-2-yl)benzimidazol-1-yl]acetamide	KI	25 nM	US-8569291: Bicyclic dihydroimidazolone CGRP receptor antagonists
N-(5’-oxo-2’-phenylspiro[1,3-dihydroindene-2,4’-1H-imidazole]-5-yl)-2-(2-oxo-3-pyridin-2-ylbenzimidazol-1-yl)acetamide	KI	35 nM	US-8569291: Bicyclic dihydroimidazolone CGRP receptor antagonists
(3S)-3’-[[2-(4-fluorophenyl)-3-oxopiperazin-1-yl]methyl]spiro[1H-pyrrolo[2,3-b]pyridine-3,7’-6,8-dihydrocyclopenta[g]quinoline]-2-one	KI	57 nM	US-8507477: 3- and 6-quinolines with N-attached heterocyclic CGRP receptor antagonists
(3S)-N-[(5R,6S,9S)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl]-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[b]pyridine]-3’-carboxamide	IC50	65 nM	US-9227973: Pyridine CGRP receptor antagonists
2-(2-oxo-3-pyridin-2-ylbenzimidazol-1-yl)-N-(5’-oxo-2’-pyridin-3-ylspiro[1,3-dihydroindene-2,4’-1H-imidazole]-5-yl)acetamide	KI	130 nM	US-8569291: Bicyclic dihydroimidazolone CGRP receptor antagonists
(3R)-2-oxo-N-(6-phenyl-5,6,7,8-tetrahydroquinolin-8-yl)spiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[b]pyridine]-3’-carboxamide	IC50	150 nM	US-9227973: Pyridine CGRP receptor antagonists
2-(2-oxo-3-pyridin-2-ylbenzimidazol-1-yl)-N-(5’-oxo-2’-pyridin-4-ylspiro[1,3-dihydroindene-2,4’-1H-imidazole]-5-yl)acetamide	KI	160 nM	US-8569291: Bicyclic dihydroimidazolone CGRP receptor antagonists
(3S)-N-[(5S,6S,9S)-5-amino-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl]-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[b]pyridine]-3’-carboxamide	IC50	290 nM	US-9227973: Pyridine CGRP receptor antagonists
(3S)-N-[(6S,9S)-6-(2,3-difluorophenyl)-6,7,8,9-tetrahydro-5H-cyclohepta[b]pyridin-9-yl]-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[b]pyridine]-3’-carboxamide	IC50	380 nM	US-9227973: Pyridine CGRP receptor antagonists
2-(2-oxo-3-pyridin-2-ylbenzimidazol-1-yl)-N-(5’-oxo-2’-pyridin-2-ylspiro[1,3-dihydroindene-2,4’-1H-imidazole]-5-yl)acetamide	KI	570 nM	US-8569291: Bicyclic dihydroimidazolone CGRP receptor antagonists

ChEMBL bioactivities

1791 potent at pChembl≥5 of 1822 total, top 50 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
11.00	Ki	0.01	nM	OLCEGEPANT
11.00	IC50	0.01	nM	CHEMBL4643006
11.00	Ki	0.01	nM	CHEMBL454791
11.00	IC50	0.01	nM	CHEMBL452966
11.00	IC50	0.01	nM	CHEMBL5810695
11.00	IC50	0.01	nM	CHEMBL5865405
11.00	IC50	0.01	nM	CHEMBL6015508
11.00	IC50	0.01	nM	CHEMBL5755575
11.00	IC50	0.01	nM	CHEMBL5978732
10.96	Ki	0.011	nM	CHEMBL2336422
10.96	Ki	0.011	nM	CHEMBL3893283
10.96	IC50	0.011	nM	CHEMBL508453
10.92	Ki	0.012	nM	CHEMBL2336424
10.89	Ki	0.013	nM	CHEMBL450668
10.89	Ki	0.0128	nM	CHEMBL450668
10.85	Ki	0.014	nM	CHEMBL2035984
10.85	Ki	0.014	nM	OLCEGEPANT
10.85	Ki	0.014	nM	CHEMBL4859941
10.82	Ki	0.015	nM	CHEMBL2336411
10.82	Ki	0.015	nM	CHEMBL3981883
10.82	Ki	0.015	nM	ATOGEPANT
10.82	Ki	0.015	nM	CHEMBL4848032
10.80	Ki	0.016	nM	CHEMBL2035985
10.77	EC50	0.017	nM	CHEMBL454791
10.77	Ki	0.017	nM	CHEMBL2431249
10.77	Ki	0.017	nM	CHEMBL3914484
10.77	IC50	0.017	nM	CHEMBL508215
10.77	Ki	0.017	nM	CHEMBL3990832
10.72	IC50	0.019	nM	CHEMBL2018517
10.72	Ki	0.019	nM	CHEMBL2431246
10.72	Ki	0.019	nM	CHEMBL4848486
10.70	IC50	0.02	nM	CHEMBL2022601
10.70	IC50	0.02	nM	OLCEGEPANT
10.70	Ki	0.02	nM	CHEMBL3114495
10.70	Ki	0.02	nM	CHEMBL264010
10.70	Ki	0.02	nM	CHEMBL2371890
10.70	Ki	0.01995	nM	CHEMBL4638112
10.70	Ki	0.02	nM	CHEMBL4638635
10.70	Ki	0.02	nM	CHEMBL4857649
10.70	IC50	0.02	nM	CHEMBL447297
10.70	Ki	0.02	nM	CHEMBL4638112
10.70	Ki	0.02	nM	CHEMBL5828757
10.70	IC50	0.02	nM	CHEMBL5740788
10.70	IC50	0.02	nM	CHEMBL5917191
10.70	IC50	0.02	nM	CHEMBL5742096
10.70	IC50	0.02	nM	CHEMBL5965987
10.70	IC50	0.02	nM	CHEMBL5760510
10.70	IC50	0.02	nM	CHEMBL5770083
10.70	IC50	0.02	nM	CHEMBL6061451
10.70	IC50	0.02	nM	CHEMBL5759145

PubChem BioAssay actives

1382 with measured affinity, of 1638 total; 50 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
N-[3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-piperidin-1-ylpiperidin-1-yl)propan-2-yl]-4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carboxamide	736593: Binding affinity to CGRP receptor (unknown origin)	ki	<0.0001	uM
N-[3-(7-chloro-1H-indazol-5-yl)-1-oxo-1-(4-piperidin-1-ylpiperidin-1-yl)propan-2-yl]-4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carboxamide	736593: Binding affinity to CGRP receptor (unknown origin)	ki	<0.0001	uM
N-[3-(7-ethyl-1H-indazol-5-yl)-1-oxo-1-(4-piperidin-1-ylpiperidin-1-yl)propan-2-yl]-4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carboxamide	736593: Binding affinity to CGRP receptor (unknown origin)	ki	<0.0001	uM
N-[(2R)-3-(4-chloro-2-oxo-3H-1,3-benzoxazol-6-yl)-1-oxo-1-(4-piperidin-1-ylpiperidin-1-yl)propan-2-yl]-4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carboxamide	736593: Binding affinity to CGRP receptor (unknown origin)	ki	<0.0001	uM
N-[(2R)-3-(4-bromo-2-oxo-3H-1,3-benzoxazol-6-yl)-1-oxo-1-(4-piperidin-1-ylpiperidin-1-yl)propan-2-yl]-4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carboxamide	736593: Binding affinity to CGRP receptor (unknown origin)	ki	<0.0001	uM
N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-piperidin-1-ylpiperidin-1-yl)propan-2-yl]-4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carboxamide	361794: Displacement of [I125]CGRP from human CGRP receptor in SK-N-MC cells	ki	<0.0001	uM
[(2R)-1-(4-cyclohexylpiperazin-1-yl)-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl] 4-(2-oxo-1H-quinolin-3-yl)piperidine-1-carboxylate	375825: Antagonist activity at human cloned CGRP receptor expressed in mouse E10 cells assessed as inhibition of CGRP-induced cAMP production	ic50	<0.0001	uM
[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-piperidin-1-ylpiperidin-1-yl)propan-2-yl] 4-(7-fluoro-2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carboxylate	375825: Antagonist activity at human cloned CGRP receptor expressed in mouse E10 cells assessed as inhibition of CGRP-induced cAMP production	ic50	<0.0001	uM
[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-piperidin-1-ylpiperidin-1-yl)propan-2-yl] 4-(8-fluoro-2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carboxylate	375825: Antagonist activity at human cloned CGRP receptor expressed in mouse E10 cells assessed as inhibition of CGRP-induced cAMP production	ic50	<0.0001	uM
[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-piperidin-1-ylpiperidin-1-yl)propan-2-yl] 4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carboxylate	375825: Antagonist activity at human cloned CGRP receptor expressed in mouse E10 cells assessed as inhibition of CGRP-induced cAMP production	ic50	<0.0001	uM
[(2R)-1-(9-methyl-3,9-diazaspiro[5.5]undecan-3-yl)-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl] 4-(2-oxo-1H-quinolin-3-yl)piperidine-1-carboxylate	375825: Antagonist activity at human cloned CGRP receptor expressed in mouse E10 cells assessed as inhibition of CGRP-induced cAMP production	ic50	<0.0001	uM
[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-piperidin-1-ylpiperidin-1-yl)propan-2-yl] 4-(2-oxo-1H-quinolin-3-yl)piperidine-1-carboxylate	375825: Antagonist activity at human cloned CGRP receptor expressed in mouse E10 cells assessed as inhibition of CGRP-induced cAMP production	ic50	<0.0001	uM
(3S)-3-[[(2S,3R)-2-[[(3S)-2-[(2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-3-methylbutanoyl]-3,4-dihydro-1H-isoquinoline-3-carbonyl]amino]-3-hydroxybutanoyl]amino]-4-[[(2S)-1-[[2-[(2S)-2-[[(2S)-1-[[(2S)-1-[[(1S)-1-carboxy-2-phenylethyl]amino]-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamoyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	257877: Displacement of [3H-propionyl-K24] from halphaCGRP expressed in human neuroblastoma SK-N-MC cells	ki	<0.0001	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]-4-(2-oxo-3H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide	1652728: Displacement of [3H]telcagepant from recombinant human CLR/RAMP1 expressed in Sf21 insect cell membranes measured after 60 mins by microbeta scintillation counting method	ki	<0.0001	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	1652728: Displacement of [3H]telcagepant from recombinant human CLR/RAMP1 expressed in Sf21 insect cell membranes measured after 60 mins by microbeta scintillation counting method	ki	<0.0001	uM
N-[(2R)-3-(3,5-dibromo-4-hydroxyphenyl)-1-oxo-1-[[(2S)-1-oxo-3-piperidin-4-yl-1-(4-pyridin-4-ylpiperazin-1-yl)propan-2-yl]amino]propan-2-yl]-4-(2-oxo-3H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide	1652728: Displacement of [3H]telcagepant from recombinant human CLR/RAMP1 expressed in Sf21 insect cell membranes measured after 60 mins by microbeta scintillation counting method	ki	<0.0001	uM
(2S)-1-[(2S)-2-[[2-[[(2S)-2-[[2-[[(2S,3S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S)-2-[[(2S,3S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-6-amino-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S,3R)-2-[[(2S)-2-[[(2S,3R)-2-[[2-[[(2S)-2-[[(2S)-2-[[(4R,7S,10S,13R,16S,22R)-22-amino-16-(2-amino-2-oxoethyl)-7-[(1R)-1-hydroxyethyl]-10-(hydroxymethyl)-13-(2-methylpropyl)-6,9,12,15,18,21-hexaoxo-1,2-dithia-5,8,11,14,17,20-hexazacyclotricosane-4-carbonyl]amino]-4-methylsulfanylbutanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxybutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-hydroxybutanoyl]amino]-5-oxopentanoyl]amino]-3-carboxypropanoyl]amino]-3-phenylpropanoyl]amino]-4-oxobutanoyl]amino]hexanoyl]amino]-3-phenylpropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-3-hydroxybutanoyl]amino]-3-phenylpropanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]propanoyl]amino]-3-methylpentanoyl]amino]acetyl]amino]-3-methylbutanoyl]amino]acetyl]amino]propanoyl]pyrrolidine-2-carboxylic acid	1336313: Displacement of [125I]hCGRPa from human recombinant CGRP receptor expressed in CHO cells measured after 90 mins by scintillation counting method	ic50	<0.0001	uM
N-[(2S,5R,8R)-5-(2-cyanopropan-2-yl)-8-(4-fluoro-2-methylphenyl)-3-oxo-2,5,6,7-tetrahydro-1H-pyrrolizin-2-yl]-3-fluoro-5-methyl-4-[(3-methyl-6-oxo-1H-pyridazin-5-yl)oxy]benzamide	1657084: Inhibition of human CLR/RAMP1	ki	<0.0001	uM
N-[2-[(2S,5R)-2-(2-cyanopropan-2-yl)-5-(3-methylphenyl)pyrrolidin-1-yl]-2-oxoethyl]-3-methyl-4-[(3-methyl-6-oxo-1H-pyridazin-5-yl)methyl]benzamide	1657084: Inhibition of human CLR/RAMP1	ki	<0.0001	uM
N-[(2R)-1-[[(2S)-6-amino-1-oxo-1-(4-pyridin-4-ylpiperazin-1-yl)hexan-2-yl]amino]-3-(7-methyl-1H-indazol-5-yl)-1-oxopropan-2-yl]-4-(2-oxo-3H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide	1652728: Displacement of [3H]telcagepant from recombinant human CLR/RAMP1 expressed in Sf21 insect cell membranes measured after 60 mins by microbeta scintillation counting method	ki	<0.0001	uM
4-[1-[5-[(2,6-dimethyl-4-pyridinyl)-methylamino]-4-[2-(2-methoxypropan-2-yl)-4-pyridinyl]-2-pyridinyl]piperidin-4-yl]-3,5-dihydro-1H-1,4-benzodiazepin-2-one	1657093: Inhibition of human CLR/RAMP1 by cAMP assay	ic50	<0.0001	uM
N-[(2-cyclobutyl-6-methyl-4-pyridinyl)methyl]-5-[(1R)-1-[(3R)-3-methyl-2-oxo-1H-pyrrolo[2,3-b]pyridin-3-yl]ethyl]pyridine-2-carboxamide	1657084: Inhibition of human CLR/RAMP1	ki	<0.0001	uM
(7S)-4-chloro-7-[2-oxo-2-[4-(2-oxo-4,5-dihydro-1H-1,3-benzodiazepin-3-yl)piperidin-1-yl]ethyl]-1,9-bis(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydroimidazo[4,5-i][2]benzazepine-2,8-dione	1776451: Displacement of [125I]CGRP from human CGRP receptor in human SK-N-MC cells measured after 2 hrs by scintillation counting analysis	ki	<0.0001	uM
(7S)-4-chloro-1-ethyl-7-[2-oxo-2-[4-(2-oxo-4,5-dihydro-1H-1,3-benzodiazepin-3-yl)piperidin-1-yl]ethyl]-9-(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydroimidazo[4,5-i][2]benzazepine-2,8-dione	1776451: Displacement of [125I]CGRP from human CGRP receptor in human SK-N-MC cells measured after 2 hrs by scintillation counting analysis	ki	<0.0001	uM
(7S)-4-chloro-7-[2-oxo-2-[4-(2-oxo-4,5-dihydro-1H-1,3-benzodiazepin-3-yl)piperidin-1-yl]ethyl]-9-(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydro-1H-imidazo[4,5-i][2]benzazepine-2,8-dione	1776451: Displacement of [125I]CGRP from human CGRP receptor in human SK-N-MC cells measured after 2 hrs by scintillation counting analysis	ki	<0.0001	uM
(7S)-4-chloro-1-methyl-7-[2-oxo-2-[4-(2-oxo-4,5-dihydro-1H-1,3-benzodiazepin-3-yl)piperidin-1-yl]ethyl]-9-(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydroimidazo[4,5-i][2]benzazepine-2,8-dione	1776451: Displacement of [125I]CGRP from human CGRP receptor in human SK-N-MC cells measured after 2 hrs by scintillation counting analysis	ki	<0.0001	uM
(7S)-4-chloro-1-methyl-7-[2-oxo-2-[4-(2-oxo-4,5-dihydro-1H-pyrido[3,2-d][1,3]diazepin-3-yl)piperidin-1-yl]ethyl]-9-(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydroimidazo[4,5-i][2]benzazepine-2,8-dione	1776451: Displacement of [125I]CGRP from human CGRP receptor in human SK-N-MC cells measured after 2 hrs by scintillation counting analysis	ki	<0.0001	uM
(7S)-4-chloro-7-[2-oxo-2-[4-(2-oxo-3H-imidazo[4,5-b]pyridin-1-yl)piperidin-1-yl]ethyl]-1,9-bis(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydroimidazo[4,5-i][2]benzazepine-2,8-dione	1776451: Displacement of [125I]CGRP from human CGRP receptor in human SK-N-MC cells measured after 2 hrs by scintillation counting analysis	ki	<0.0001	uM
(7S)-4-chloro-7-[2-oxo-2-[4-(2-oxo-4,5-dihydro-1H-1,3-benzodiazepin-3-yl)piperidin-1-yl]ethyl]-9-(2,2,2-trifluoroethyl)-3,6,7,10-tetrahydropyrazolo[3,4-i][2]benzazepin-8-one	1776451: Displacement of [125I]CGRP from human CGRP receptor in human SK-N-MC cells measured after 2 hrs by scintillation counting analysis	ki	<0.0001	uM
2-[(8R)-8-(3,5-difluorophenyl)-10-oxo-6,9-diazaspiro[4.5]decan-9-yl]-N-[(2R)-2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl]acetamide	665599: Displacement of [125I]CGRP from human recombinant CALCRL/RAMP1 receptor expressed in HEK293 cells after 3 hrs	ki	<0.0001	uM
2-[(6R)-6-(3,5-difluorophenyl)-3,3-dimethyl-2-oxopiperazin-1-yl]-N-[(2R)-2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl]acetamide	772350: Displacement of [125I]-hCGRP from human CGRP receptor expressed in HEK293 cells	ki	<0.0001	uM
2-(2,10-dioxo-1,3,9-triazatricyclo[6.3.1.04,12]dodeca-4,6,8(12)-trien-3-yl)-N-[(2S)-2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl]acetamide	412189: Displacement of [125I]hCGRP from human CGRP receptor expressed in HEK293 cells coexpressing RAMP1	ki	<0.0001	uM
(3S)-3-[[(2S,3R)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-3-methylbutanoyl]pyrrolidine-2-carbonyl]amino]-3-hydroxybutanoyl]amino]-4-[[(2S)-1-[[2-[(2S)-2-[[(2S)-1-[[(2S)-1-[[(1S)-1-carboxy-2-phenylethyl]amino]-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamoyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	257877: Displacement of [3H-propionyl-K24] from halphaCGRP expressed in human neuroblastoma SK-N-MC cells	ki	<0.0001	uM
N-[(2S)-1-[[(2R)-6-amino-1-oxo-1-(4-pyridin-4-ylpiperazin-1-yl)hexan-2-yl]amino]-3-(3,5-dibromo-4-hydroxyphenyl)-1-oxopropan-2-yl]-4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidine-1-carboxamide	254577: Antagonistic activity against calcitonin gene related peptide receptor determined by measuring the formation of cyclic AMP in SK-N-MC cells	kd	<0.0001	uM
(3S)-3-[[(2S,3R)-2-[[2-[[(2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-3-methylbutanoyl]amino]-2-methylpropanoyl]amino]-3-hydroxybutanoyl]amino]-4-[[(2S)-1-[[2-[(2S)-2-[[(2S)-1-[[(2S)-1-[[(1S)-1-carboxy-2-phenylethyl]amino]-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]carbamoyl]pyrrolidin-1-yl]-2-oxoethyl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-oxobutanoic acid	257877: Displacement of [3H-propionyl-K24] from halphaCGRP expressed in human neuroblastoma SK-N-MC cells	ki	<0.0001	uM
(3S)-3’-[3-[(8R)-8-(3,5-difluorophenyl)-6,8-dimethyl-10-oxo-6,9-diazaspiro[4.5]decan-9-yl]prop-1-ynyl]spiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[b]pyridine]-2-one	772350: Displacement of [125I]-hCGRP from human CGRP receptor expressed in HEK293 cells	ki	<0.0001	uM
(3S)-3’-[(E)-3-[(8R)-8-(3,5-difluorophenyl)-6,8-dimethyl-10-oxo-6,9-diazaspiro[4.5]decan-9-yl]prop-1-enyl]spiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[b]pyridine]-2-one	772350: Displacement of [125I]-hCGRP from human CGRP receptor expressed in HEK293 cells	ki	<0.0001	uM
(3S)-3’-[3-[(8R)-8-(3,5-difluorophenyl)-6,8-dimethyl-10-oxo-6,9-diazaspiro[4.5]decan-9-yl]propyl]spiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[b]pyridine]-2-one	772350: Displacement of [125I]-hCGRP from human CGRP receptor expressed in HEK293 cells	ki	<0.0001	uM
4-(8-fluoro-2-oxo-1,4-dihydroquinazolin-3-yl)-N-[(2R)-3-(7-methyl-1H-indazol-5-yl)-1-oxo-1-(4-piperidin-1-ylpiperidin-1-yl)propan-2-yl]piperidine-1-carboxamide	361794: Displacement of [I125]CGRP from human CGRP receptor in SK-N-MC cells	ki	<0.0001	uM
2-[(6S)-6-(2,6-difluorophenyl)-3,3-dimethyl-2-oxopiperidin-1-yl]-N-[(2S)-2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl]acetamide	447514: Displacement of [125I]hCGRP from human cloned CGRP receptor expressed in HEK293 cells	ki	<0.0001	uM
3-[[(3R)-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,7’-6,8-dihydrocyclopenta[g]quinoline]-2’-yl]methyl]-1,3,9-triazatricyclo[6.3.1.04,12]dodeca-4,6,8(12)-triene-2,10-dione	475154: Displacement of [125I]human CLR from human CGRP expressed in HEK293 cells coexpressing human RAMP1	ki	<0.0001	uM
2-[(8R)-8-(3,5-difluorophenyl)-6,8-dimethyl-10-oxo-6,9-diazaspiro[4.5]decan-9-yl]-N-[(2R)-2’-oxospiro[1,3-dihydroindene-2,3’-1H-pyrrolo[2,3-b]pyridine]-5-yl]acetamide	772350: Displacement of [125I]-hCGRP from human CGRP receptor expressed in HEK293 cells	ki	<0.0001	uM
Rimegepant	710367: Displacement of [125I]-CGRP from CGRP receptor in human SK-N-MC cells after 2 hrs by gamma scintillation counter analysis	ki	<0.0001	uM
N-[[(1R)-2,3-dihydro-1H-inden-1-yl]methyl]-2,2-dimethyl-N-[[(3S)-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,7’-6,8-dihydrocyclopenta[g]quinoline]-3’-yl]methyl]propanamide	526712: Displacement of [125I]hCGRP from human cloned CGRP receptor expressed in HEK293 cells	ki	<0.0001	uM
Zavegepant	754795: Displacement of [125I]-CGRP from CGRP receptor in human SK-N-MC cell membranes after 2 hrs by scintillation counting analysis	ki	<0.0001	uM
N-[(6S,9R)-6-(2,3-difluorophenyl)-3-(2-methyloxolan-2-yl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]-2-oxospiro[1H-pyrido[2,3-d][1,3]oxazine-4,4’-piperidine]-1’-carboxamide	594894: Displacement of [125I]-CGRP from human recombinant CGRP receptor	ki	<0.0001	uM
N-[(6S,9R)-6-(2,3-difluorophenyl)-3-(2-methoxypropan-2-yl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]-4-(2-oxo-3H-imidazo[4,5-b]pyridin-1-yl)piperidine-1-carboxamide	594894: Displacement of [125I]-CGRP from human recombinant CGRP receptor	ki	<0.0001	uM
N-[(6S,9R)-6-(2,3-difluorophenyl)-3-(3-methoxypentan-3-yl)-6,7,8,9-tetrahydro-5H-imidazo[1,2-a]azepin-9-yl]-2-oxospiro[1H-pyrido[2,3-d][1,3]oxazine-4,4’-piperidine]-1’-carboxamide	594894: Displacement of [125I]-CGRP from human recombinant CGRP receptor	ki	<0.0001	uM
2-[(8R)-8-(3,5-difluorophenyl)-8-methyl-10-oxo-6,9-diazaspiro[4.5]decan-9-yl]-N-[(3S)-2-oxospiro[1H-pyrrolo[2,3-b]pyridine-3,6’-5,7-dihydrocyclopenta[b]pyridine]-3’-yl]acetamide	665599: Displacement of [125I]CGRP from human recombinant CALCRL/RAMP1 receptor expressed in HEK293 cells after 3 hrs	ki	<0.0001	uM
(2S)-2-[(7-methyl-1H-indazol-5-yl)methyl]-4-[4-(2-oxo-1,4-dihydroquinazolin-3-yl)piperidin-1-yl]-1-(4-piperidin-1-ylpiperidin-1-yl)butane-1,4-dione	656730: Antagonist activity at human CGRP receptor expressed in human SK-N-MC cells assessed as inhibition of CGRP-stimulated cAMP production	ic50	<0.0001	uM

CTD chemical–gene interactions

31 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, decreases methylation	4
bisphenol A	affects expression, decreases expression	2
trichostatin A	increases expression	2
nickel sulfate	increases expression	2
sodium arsenite	decreases expression	1
cobaltous chloride	decreases expression	1
perfluorooctanoic acid	increases expression	1
ferrous chloride	decreases expression	1
Am 580	decreases expression	1
CGP 52608	affects binding, increases reaction	1
perfluoro-n-nonanoic acid	increases expression	1
entinostat	increases expression	1
olcegepant	affects binding, decreases activity	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
abrine	decreases expression	1
dorsomorphin	affects cotreatment, increases expression	1
telcagepant	affects binding, decreases activity	1
incobotulinumtoxinA	increases expression	1
Rosiglitazone	decreases expression	1
Vorinostat	increases expression, affects cotreatment	1
Leflunomide	decreases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	decreases methylation, increases methylation	1
Cadmium	decreases expression	1
Dinitrochlorobenzene	increases expression	1
Doxorubicin	decreases expression	1
Eugenol	increases expression	1
Colforsin	decreases reaction, increases expression	1
Tobacco Smoke Pollution	decreases expression	1
Cyclosporine	decreases expression	1

ChEMBL screening assays

196 unique, capped per target: 131 binding, 65 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL2040005	Binding	Displacement of [125I]CGRP from human recombinant CALCRL/RAMP1 receptor expressed in HEK293 cells after 3 hrs	MK-8825: a potent and selective CGRP receptor antagonist with good oral activity in rats. — Bioorg Med Chem Lett
CHEMBL4612975	Functional	Antagonist activity at human CGRP receptor in human SK-N-MC cells assessed as inhibition of CGRP-induced cAMP production preincubated for 30 mins followed by CGRP addition and measured after 30 mins by HTRF assay	Structure-Based Drug Discovery of N-((R)-3-(7-Methyl-1H-indazol-5-yl)-1-oxo-1-(((S)-1-oxo-3-(piperidin-4-yl)-1-(4-(pyridin-4-yl)piperazin-1-yl)propan-2-yl)amino)propan-2-yl)-2’-oxo-1’,2’-dihydrospiro[piperidine-4,4’-pyrido[2,3-d][1,3]oxazine]-1-carboxamide (HTL22562): A Calcitonin Gene-Related Peptide Receptor Antagonist for Acute Treatment of Migraine. — J Med Chem

Cellosaurus cell lines

11 cell lines: 6 spontaneously immortalized cell line, 5 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_C0SA	ACTOne CALCRL	Transformed cell line	Female
CVCL_E4J2	Genomeditech HEK-293 H_CALCRL+RAMP1 Reporter	Transformed cell line	Female
CVCL_H396	CHO-K1/AM1	Spontaneously immortalized cell line	Female
CVCL_H397	CHO-K1/AM2/Galpha15	Spontaneously immortalized cell line	Female
CVCL_KU85	cAMP Hunter CHO-K1 CALCRL-RAMP1 Gs	Spontaneously immortalized cell line	Female
CVCL_KU86	cAMP Hunter CHO-K1 CALCRL-RAMP3 Gs	Spontaneously immortalized cell line	Female
CVCL_KW49	PathHunter CHO-K1 CALCRL-RAMP2 beta-arrestin	Spontaneously immortalized cell line	Female
CVCL_KW50	PathHunter CHO-K1 CALCRL-RAMP3 beta-arrestin	Spontaneously immortalized cell line	Female
CVCL_ZK45	GeneBLAzer CALCRL:RAMP1-CRE-bla FreeStyle 293F	Transformed cell line	Female
CVCL_ZK46	GeneBLAzer CALCRL:RAMP2-CRE-bla FreeStyle 293F	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT04586348	PHASE4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	PHASE4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02559102	PHASE3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	PHASE3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	PHASE3	RECRUITING	Reducing Missed Appointments
NCT07377032	PHASE3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT02909959	PHASE2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	PHASE2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	PHASE2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT00503191	PHASE1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	PHASE1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01783041	PHASE2/PHASE3	COMPLETED	Effect of Early L-Carnitine Supplementation on Neurodevelopmental Outcomes in Very Preterm Infants
NCT05767385	PHASE2/PHASE3	RECRUITING	Fetal Cerebrovascular Autoregulation in Congenital Heart Disease and Association With Neonatal Neurobehavior
NCT05675098	EARLY_PHASE1	NOT_YET_RECRUITING	Central Nervous System Stimulants and Physical Function in Children With Cerebral Palsy
NCT00783783	Not specified	COMPLETED	CYP2D6 Pharmacogenetics in Risperidone-Treated Children
NCT01778504	Not specified	RECRUITING	Studying Childhood-onset Behavioral, Psychiatric, and Developmental Disorders
NCT01850784	Not specified	UNKNOWN	High Energy Formula Feeding in Infants With Congenital Heart Disease
NCT01922791	Not specified	COMPLETED	Nutrition and Pregnancy Intervention Study
NCT01942525	Not specified	UNKNOWN	Influence of Intrauterine Growth Restriction on Amplitude-integrated EEG in Preterm Infants
NCT02003170	Not specified	COMPLETED	Etiology and Early Diagnosis of Neurodevelopmental Disorders
NCT02118649	Not specified	ACTIVE_NOT_RECRUITING	Enhancing Behavior and Brain Response to Visual Targets Using a Computer Game
NCT02557191	Not specified	TERMINATED	Biomarkers, Neurodevelopment and Preterm Infants
NCT02690675	Not specified	COMPLETED	Iron Supplement Effect on Child Development
NCT02694003	Not specified	COMPLETED	Better Nights, Better Days for Children With Neurodevelopment Disorders
NCT02792894	Not specified	COMPLETED	Family Networks (FaNs) for Children With Developmental Disorders and Delays
NCT02871674	Not specified	UNKNOWN	Good Night Project: Behavioural Sleep Interventions for Children With ADHD: A Randomised Controlled Trial
NCT02887157	Not specified	COMPLETED	Analyzing Retinal Microanatomy in ROP
NCT02898298	Not specified	COMPLETED	Positive Emotion Regulation Training in Children, Adolescents and Young Adults With and Without Developmental Disorder
NCT02912780	Not specified	UNKNOWN	Introduction of Microsystems in a Level 3 Neonatal Intensive Care Unit
NCT03023293	Not specified	COMPLETED	n-3 PUFAs, Irisin and Maternal Glucose Metabolism From Pregnancy to Postpartum
NCT03023644	Not specified	COMPLETED	Improving Neurodevelopmental Outcomes in Children With Congenital Heart Disease: An Intervention Study
NCT03032991	Not specified	UNKNOWN	Early Biomarkers of Neurodevelopment in Offspring of Diabetic Mothers
NCT03088189	Not specified	TERMINATED	Effect of Parental Peri-conceptional Vitamin B12 Supplementation on Infant Neurocognitive Development in Offspring
NCT03096028	Not specified	COMPLETED	Developmental Origins of Mental Health Disorders
NCT03148782	Not specified	COMPLETED	Brain Plasticity Underlying Acquisition of New Organizational Skills in Children-R61 Phase
NCT03172104	Not specified	COMPLETED	Neurobehavioural Development of Infants Born <30 Weeks Gestational Age Between Birth and Five Years of Age
NCT03222375	Not specified	RECRUITING	SQUED™ Series 28.1 Home-use and Treatment of Autowave Reverberator of Autism
NCT03229928	Not specified	COMPLETED	Clinical Testing of a Real-Time Behavior Measurement Tool: Measuring Outcomes for CHAnge
NCT03232489	Not specified	UNKNOWN	Study for the Evaluation of the Feasibility of Applying Advanced MRI Scanning in Pediatric Clinical Practice