Nortriptyline

Summary

Nortriptyline (CHEMBL445) is an approved small-molecule antidepressant (ATC N06AA10) targeting ADRA1A, KCNJ6, and KCNJ5; indicated across 12 conditions including depressive disorder and gastroesophageal reflux disease.

At a glance

• Status: Approved (max clinical phase 4)
• Modality: Small molecule
• ATC class: N06AA10
• Targets: 6 (ADRA1A, KCNJ6, KCNJ5…)
• Indications: 12 conditions
• Clinical trials: 30
• Chemistry: 263.4 Da · C19H21N

Identifiers

Drug identity and classification

Field	Value
ChEMBL ID	CHEMBL445
Name	Nortriptyline
Type	Small molecule
Max phase	4
FDA approved	yes
PubChem CID	4543
ChEBI	CHEBI:7640
ATC	N06AA10
Molecular formula	C19H21N
Molecular weight	263.4
InChIKey	PHVGLTMQBUFIQQ-UHFFFAOYSA-N

SMILES: CNCCC=C1C2=CC=CC=C2CCC3=CC=CC=C31

IUPAC name: N-methyl-3-(2-tricyclo[9.4.0.03,8]pentadeca-1(15),3,5,7,11,13-hexaenylidene)propan-1-amine

ChEBI definition: An organic tricyclic compound that is 10,11-dihydro-5H-dibenzo[a,d][7]annulene substituted by a 3-(methylamino)propylidene group at position 5. It is an active metabolite of amitriptyline.

Pharmacological roles (ChEBI): antidepressant, adrenergic uptake inhibitor, analgesic, antineoplastic agent, apoptosis inducer.

Other ChEBI roles (chemical / environmental): drug metabolite.

Also known as: Allegron, Aventyl, Desitriptilina, Lumbeck, Motipress, Motival, NCI-169453, Noramitriptyline, Nortrilen, Nortriptilina, Nortriptyline, NSC-757234

Parent form; salt/anhydrous children: CHEMBL1201156

Patent coverage: 8,327 distinct patent families (31,234 SureChEMBL compound mentions), from 2 matched compound structure(s). One matched structure accounts for 31,032 (99%) of the total. Mentions count patents naming the compound (not distinct inventions), so promiscuous / reference molecules inflate the mention figure — families are the dedup metric.

Targets

Targets

Primary targets (GtoPdb curated mechanism): the Cancer dependency column is the DepMap CRISPR fitness signal (% of screened cell lines dependent on the target).

Gene	Target	Action	pAffinity	Cancer dependency	UniProt
ADRA1A	α1A-adrenoceptor	Antagonist	8.2		P35348
KCNJ6	Kir3.2	Antagonist	3.9	0.1%	P48051
KCNJ5	Kir3.4	Antagonist	3.4	0%	P48544
KCNJ10	Kir4.1	Antagonist	4.8	0.2%	P78508
SLC6A2	NET	Inhibition	8.2	0.4%	P23975
SLC6A4	SERT	Inhibition	8.16	0.7%	P31645

Broader ChEMBL bioactivity targets: 57 (assay-derived). Sample: Prelamin-A/C, Inositol monophosphatase 1, Thrombopoietin, NPC intracellular cholesterol transporter 1, Ras-related protein Rab-9A, Muscarinic acetylcholine receptor M4, 5-hydroxytryptamine receptor 2B, Alpha-2A adrenergic receptor, Alpha-2C adrenergic receptor, Histamine H2 receptor.

Bioactivity

ChEMBL activities: 103 potent at pChembl ≥ 5 of 129 total. Top 30 by potency (10 = 0.1 nM, 6 = 1 µM):

Target	pChembl	Type	Value	Unit	Activity ID
P43140	10.4	IC50	0.04	nM	CHEMBL_ACT_762578
P31390	10.3	IC50	0.05	nM	CHEMBL_ACT_762579
SLC6A2	8.5	Ki	3.18	nM	CHEMBL_ACT_7740010
SLC6A2	8.49	IC50	3.21	nM	CHEMBL_ACT_7740009
HRH1	8.23	Ki	5.86	nM	CHEMBL_ACT_7740100
SLC6A2	8.2	Ki	6.3	nM	CHEMBL_ACT_449269
SLC6A4	8.16	Ki	6.98	nM	CHEMBL_ACT_7742234
HTR2C	8.09	Ki	8.17	nM	CHEMBL_ACT_7742226
CHRM4	7.89	Ki	13	nM	CHEMBL_ACT_7740134
SLC6A4	7.89	IC50	13	nM	CHEMBL_ACT_7742233
HTR2A	7.82	Ki	15	nM	CHEMBL_ACT_7742222
HTR2C	7.8	IC50	16	nM	CHEMBL_ACT_7742225
HTR2B	7.76	AC50	17.2	nM	CHEMBL_ACT_25164015
HTR2A	7.76	AC50	17.2	nM	CHEMBL_ACT_25173489
HRH1	7.75	AC50	18	nM	CHEMBL_ACT_25212155
CHRM1	7.7	Ki	20	nM	CHEMBL_ACT_7740128
CHRM5	7.7	Ki	20	nM	CHEMBL_ACT_7740136
SLC6A2	7.6	AC50	25.3	nM	CHEMBL_ACT_25144653
CHRM5	7.57	IC50	27	nM	CHEMBL_ACT_7740135
ADRA2C	7.52	Ki	30	nM	CHEMBL_ACT_7740002
LMNA	7.45	Potency	35.5	nM	CHEMBL_ACT_3650056
ADRA1A	7.44	AC50	36	nM	CHEMBL_ACT_25217826
CHRM3	7.44	Ki	36	nM	CHEMBL_ACT_7740132
ADRA2B	7.37	Ki	43	nM	CHEMBL_ACT_7740000
HRH1	7.3	IC50	50	nM	CHEMBL_ACT_7740099
HTR2A	7.29	IC50	51	nM	CHEMBL_ACT_7742221
DRD3	7.21	Ki	61	nM	CHEMBL_ACT_7740070
CHRM1	7.09	IC50	82	nM	CHEMBL_ACT_7740127
HTR2B	7.07	Ki	86	nM	CHEMBL_ACT_7742224
ADRA2B	7.03	IC50	94	nM	CHEMBL_ACT_7739999

Target pathways

Aggregated over 6 target gene(s): ADRA1A, KCNJ6, KCNJ5, KCNJ10, SLC6A2, SLC6A4.

Top Reactome pathways

31 total, by targets touching each:

Pathway	Targets	Genes
Transmission across Chemical Synapses	4	KCNJ10, KCNJ5, KCNJ6, SLC6A4
Neuronal System	4	KCNJ10, KCNJ5, KCNJ6, SLC6A4
Neurotransmitter receptors and postsynaptic signal transmission	3	KCNJ10, KCNJ5, KCNJ6
Activation of G protein gated Potassium channels	3	KCNJ10, KCNJ5, KCNJ6
G protein gated Potassium channels	3	KCNJ10, KCNJ5, KCNJ6
Inwardly rectifying K+ channels	3	KCNJ10, KCNJ5, KCNJ6
Potassium Channels	3	KCNJ10, KCNJ5, KCNJ6
GABA receptor activation	3	KCNJ10, KCNJ5, KCNJ6
GABA B receptor activation	3	KCNJ10, KCNJ5, KCNJ6
Activation of GABAB receptors	3	KCNJ10, KCNJ5, KCNJ6
Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits	3	KCNJ10, KCNJ5, KCNJ6
SLC-mediated transport of neurotransmitters	2	SLC6A2, SLC6A4
Neurotransmitter clearance	1	SLC6A4
Potassium transport channels	1	KCNJ10
Signal Transduction	1	ADRA1A
Disease	1	SLC6A2
Signaling by GPCR	1	ADRA1A
Class A/1 (Rhodopsin-like receptors)	1	ADRA1A
Amine ligand-binding receptors	1	ADRA1A
Serotonin clearance from the synaptic cleft	1	SLC6A4
Transport of small molecules	1	SLC6A2
GPCR downstream signalling	1	ADRA1A
Adrenoceptors	1	ADRA1A
G alpha (q) signalling events	1	ADRA1A
G alpha (12/13) signalling events	1	ADRA1A
R-HSA-425366	1	SLC6A2
SLC-mediated transmembrane transport	1	SLC6A2
GPCR ligand binding	1	ADRA1A
SLC transporter disorders	1	SLC6A2
Defective SLC6A2 causes orthostatic intolerance (OI)	1	SLC6A2

Dominant GO biological processes

GO term	Targets
response to xenobiotic stimulus	3
potassium ion transport	3
regulation of monoatomic ion transmembrane transport	3
potassium ion import across plasma membrane	3
monoatomic ion transport	3
monoatomic ion transmembrane transport	3
potassium ion transmembrane transport	2
monoatomic cation transmembrane transport	2
neurotransmitter transport	2
amino acid transport	2
obsolete monoamine transport	2
sodium ion transmembrane transport	2
transmembrane transport	2
neurotransmitter reuptake	2
MAPK cascade	1

Indications & clinical

Indications

12 indications (2 at ChEMBL trial phase 4). Phase below is the highest clinical-trial phase recorded for this drug against each disease — not the molecule’s overall approval status (that is in the Summary).

Indication	Trial phase	MONDO	EFO
depressive disorder	4	MONDO:0002050	MONDO:0002050
gastroesophageal reflux disease	3	MONDO:0007186	EFO:0003948
anxiety	3	MONDO:0011918	EFO:0005230
gastroparesis	3	MONDO:0006769	EFO:1000948
dementia	3	MONDO:0001627	HP:0000726
dyspepsia	3	MONDO:0002268	EFO:0008533
irritable bowel syndrome	2	MONDO:0005052	EFO:0000555
nicotine dependence	2	MONDO:0008575	EFO:0003768
psoriasis	2	MONDO:0005083	EFO:0000676
temporomandibular joint disorder	2	MONDO:0005473	EFO:0005279

2 further indication records had no mapped disease name (EFO/MeSH-only) or were duplicates, and are omitted.

Clinical trials

Total trials: 30.

Phase distribution

Phase	Trials
PHASE4	12
PHASE2	7
PHASE3	5
Not specified	4
PHASE1/PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05582837	PHASE4	RECRUITING	Treatment of Meniere’s Disease With Migraine Medications
NCT06799169	PHASE4	ACTIVE_NOT_RECRUITING	Management of Acute Tinnitus With Migraine Medications
NCT00000378	PHASE4	COMPLETED	Antidepressant Treatment of Melancholia in Late Life
NCT00021528	PHASE4	COMPLETED	Sequenced Treatment Alternatives to Relieve Depression (STAR*D)
NCT00045916	PHASE4	COMPLETED	Optimizing Electroconvulsive Therapy for Depression
NCT00660062	PHASE4	TERMINATED	Relapse Prevention With Escitalopram or Nortriptyline Following Electro-Convulsive Treatment (DUAG-7)
NCT02237937	PHASE4	UNKNOWN	Optimizing Antidepressant Treatment by Genotype-dependent Adjustment of Medication According to the ABCB1 Gene
NCT02260388	PHASE4	COMPLETED	Patient Assisted Intervention for Neuropathy: Comparison of Treatment in Real Life Situations
NCT02901249	PHASE4	COMPLETED	Cost- Effectiveness and Quality of Life Assessment in Major Depression Disorder
NCT02918097	PHASE4	COMPLETED	Cost- Effectiveness and Quality of Life Assessment in Bipolar Disorder Depressive Episode
NCT04226365	PHASE4	TERMINATED	Pediatric Concussion Outcomes
NCT04404439	PHASE4	COMPLETED	Treatment of Tinnitus With Migraine Medications
NCT00004390	PHASE3	COMPLETED	Phase III Randomized Controlled Study of Morphine and Nortriptyline in the Management of Postherpetic Neuralgia
NCT01065649	PHASE3	COMPLETED	Effect of Nortriptyline in Cortical Representation of Heartburn in Nonerosive Reflux Disease (NERD) Patients
NCT02374567	PHASE3	TERMINATED	Pharmacovigilance in Gerontopsychiatric Patients
NCT03652571	PHASE3	TERMINATED	Nortriptyline for the Treatment of Functional Dyspepsia
NCT03652870	PHASE3	COMPLETED	Antidepressants Trial in Parkinson’s Disease
NCT00009672	PHASE2	COMPLETED	Pain Treatment for Sciatica
NCT00018148	PHASE2	COMPLETED	Combined Nortriptyline and Transdermal Nicotine for Smoking Cessation
NCT00062738	PHASE2	COMPLETED	Treatment of Depression in Parkinson’s Disease Trial
NCT00066937	PHASE2	COMPLETED	Comparison of Psychological and Pharmacological Treatments for Pain Due to Temporomandibular Joint Disorder (TMD)
NCT00612807	PHASE1/PHASE2	COMPLETED	Treatment of Mood and Marriage Study (TOMMS)
NCT00796211	PHASE2	COMPLETED	A Single-Center Exploratory Study to Assess the Activity of CRx-197-002 in Plaque Psoriasis
NCT01268709	PHASE2	COMPLETED	Effect of Doxepin and Nortriptyline on Irritable Bowel Syndrome
NCT03844412	PHASE2	COMPLETED	Vestibulodynia: Understanding Pathophysiology and Determining Appropriate Treatments
NCT00721331	PHASE1	COMPLETED	A Phase I Study to Assess the Safety and Tolerability of Topical CRx-197 Formulations in Healthy Volunteers
NCT00000377	Not specified	COMPLETED	Preventing the Return of Depression in Elderly Patients
NCT00547703	Not specified	TERMINATED	Effect of Nortriptyline on Abdominal Pain/Discomfort and Quality of Life in Patients With Nonulcer Dyspepsia
NCT01896349	Not specified	UNKNOWN	Interpersonal Psychotherapy for Treatment Resistant Depression
NCT02169830	Not specified	TERMINATED	Trial of Nortriptyline and Topiramate in the Initial Treatment of Vestibular Migraine

Clinical evidence (CIViC)

No CIViC predictive evidence (expected for non-precision-medicine drugs).

Pharmacology

Pharmacogenomics

PharmGKB dosing guidelines (2) — CPIC / DPWG genotype-guided dosing for this drug (drug × pharmacogene):

Guideline	Source	Gene(s)	Dosing	Recommendation
Annotation of DPWG Guideline for nortriptyline and CYP2D6	DPWG	CYP2D6	yes	yes
Annotation of CPIC Guideline for nortriptyline and CYP2D6	CPIC	CYP2D6	yes	yes

PharmGKB also curates 9 clinical and 85 variant annotation(s) for this drug (gene-keyed; see PharmGKB).

Related molecules

Related molecules

Molecules sharing ≥1 of this drug’s curated primary targets, merged from two biobtree sources and ranked by shared-target count, then clinical phase: ChEMBL clinical-stage candidates (development phase ≥2) and PubChem drug-class bioactivity (approved / known drugs acting on the target). Deduplicated by drug name; the drug’s own salt forms are excluded. Note: for a drug with few primary targets a shared-target match can reflect off-target / promiscuous binding rather than the same therapeutic mechanism — the phase ordering surfaces bona-fide therapeutics first.

809 molecules share ≥1 primary target. Top 60 by shared-target count:

Molecule	Source	Status	Shared targets
IMIPRAMINE	ChEMBL + PubChem	Phase 4 (approved)	ADRA1A, KCNJ5, SLC6A2, SLC6A4
MEFLOQUINE	ChEMBL + PubChem	Phase 4 (approved)	ADRA1A, KCNJ5, SLC6A2, SLC6A4
PROPAFENONE	ChEMBL + PubChem	Phase 4 (approved)	ADRA1A, KCNJ5, SLC6A2, SLC6A4
ACLIDINIUM BROMIDE	ChEMBL + PubChem	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
AMITRIPTYLINE	ChEMBL + PubChem	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
CHENODIOL	ChEMBL + PubChem	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
CRIZOTINIB	ChEMBL + PubChem	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
DIHYDROERGOTAMINE	ChEMBL + PubChem	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
GENTIAN VIOLET	ChEMBL + PubChem	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
OLODATEROL	ChEMBL + PubChem	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
PIMAVANSERIN	ChEMBL + PubChem	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
PODOFILOX	ChEMBL + PubChem	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
PROPOXYPHENE	ChEMBL + PubChem	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
PYRAZINAMIDE	ChEMBL + PubChem	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
REGORAFENIB	ChEMBL + PubChem	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
Tadalafil	ChEMBL + PubChem	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
Vorapaxar	ChEMBL + PubChem	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
ACETOPHENAZINE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
AMIODARONE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
AMOXAPINE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
ARIPIPRAZOLE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
ASENAPINE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
ASTEMIZOLE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
ATRACURIUM	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
AZELASTINE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
BAZEDOXIFENE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
BENFLUOREX	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
BENZPHETAMINE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
BENZTROPINE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
BENZYDAMINE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
BEPRIDIL	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
BOSUTINIB	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
BREXPIPRAZOLE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
BROMPERIDOL	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
CABERGOLINE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
CALCIPOTRIENE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
CALCITRIOL	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
CARVEDILOL	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
CHLORHEXIDINE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
CHLORPHENIRAMINE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
CHLORPROMAZINE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
CHLORPROTHIXENE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
CINNARIZINE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
CITALOPRAM	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
CLEMASTINE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
CLOMIPHENE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
CLOMIPRAMINE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
CLOZAPINE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
COBIMETINIB	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
CYCLOBENZAPRINE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
CYPROHEPTADINE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
DEQUALINIUM	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
DESIPRAMINE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
DESLORATADINE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
DEXTROMETHORPHAN	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
DIBENZEPIN	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
DIETHYLSTILBESTROL	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
DIPHENHYDRAMINE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
DOBUTAMINE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4
DOMPERIDONE	ChEMBL	Phase 4 (approved)	ADRA1A, SLC6A2, SLC6A4