Identification

Name
Nomifensine
Accession Number
DB04821
Type
Small Molecule
Groups
Withdrawn
Description

Nomifensine, formerly marketed as Merital capsules, was associated with an increased incidence of hemolytic anemia. The approved application holder removed Merital capsules from the market on January 23, 1986. FDA published a notice of its determination that Merital capsules were removed from the market for safety reasons (see the Federal Register of June 17, 1986 (51 FR 21981)). Approval of the NDA for Merital capsules was withdrawn on March 20, 1992 (see the Federal Register of March 20, 1992 (57 FR 9729)). Also withdrawn from the Canadian and UK markets.

Structure
Thumb
Synonyms
  • (+-)-nomifensin
  • (+-)-nomifensine
  • (+)-nomifensine
  • (+)-nomiphensine
  • (R)-1,2,3,4-Tetrahydro-2-methyl-4-phenyl-8-isoquinolinamine
  • 2-Methyl-4-phenyl-1,2,3,4-tetrahydro-8-isoquinolinamine
  • 8-Amino-1,2,3,4-tetrahydro-2-methyl-4-phenylisochinolin
  • 8-Amino-1,2,3,4-tetrahydro-2-methyl-4-phenylisoquinoline
  • 8-Amino-2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinoline
  • Nomifensin
  • Nomifensina
  • Nomifensinum
International/Other Brands
Linamiphen / Merital / Nomifenison
Categories
UNII
1LGS5JRP31
CAS number
24526-64-5
Weight
Average: 238.3275
Monoisotopic: 238.146998586
Chemical Formula
C16H18N2
InChI Key
XXPANQJNYNUNES-UHFFFAOYSA-N
InChI
InChI=1S/C16H18N2/c1-18-10-14(12-6-3-2-4-7-12)13-8-5-9-16(17)15(13)11-18/h2-9,14H,10-11,17H2,1H3
IUPAC Name
2-methyl-4-phenyl-1,2,3,4-tetrahydroisoquinolin-8-amine
SMILES
CN1CC(C2=CC=CC=C2)C2=C(C1)C(N)=CC=C2

Pharmacology

Indication
Not Available
Structured Indications
Not Available
Pharmacodynamics

Nomifensine is a dopamine reuptake inhibitor test-marketed in the United States by Hoechst AG (now Novartis) that increases the amount of synaptic dopamine available to receptors by blocking dopamine's re-uptake transporter. Nomifensine is now mainly used in scientific research, particularly in studies involving dopamine release in response to addiction.

Mechanism of action
TargetActionsOrganism
USodium-dependent noradrenaline transporterNot AvailableHuman
USodium-dependent dopamine transporterNot AvailableHuman
UAmine oxidase [flavin-containing] BNot AvailableHuman
UAmine oxidase [flavin-containing] ANot AvailableHuman
UMyeloperoxidaseNot AvailableHuman
USodium-dependent serotonin transporterNot AvailableHuman
USynaptic vesicular amine transporterNot AvailableHuman
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life
Not Available
Clearance
Not Available
Toxicity

A likely cause of nomifensine toxicity is the aromatic amine group, as compounds containing this chemical substructure are notorious for producing toxic metabolites.

Affected organisms
  • Humans and other mammals
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
DrugInteractionDrug group
VemurafenibThe risk or severity of QTc prolongation can be increased when Vemurafenib is combined with Nomifensine.Approved
Food Interactions
Not Available

References

Synthesis Reference
US3577424
General References
Not Available
External Links
PubChem Compound
4528
PubChem Substance
46505804
ChemSpider
4371
BindingDB
50005548
ChEBI
116225
ChEMBL
CHEMBL273575
Therapeutic Targets Database
DCL000339
Wikipedia
Nomifensine
ATC Codes
N06AX04 — Nomifensine

Clinical Trials

Clinical Trials
Not Available

Pharmacoeconomics

Manufacturers
Not Available
Packagers
Not Available
Dosage forms
Not Available
Prices
Not Available
Patents
Not Available

Properties

State
Solid
Experimental Properties
PropertyValueSource
melting point (°C)180 °CPhysProp
Predicted Properties
PropertyValueSource
Water Solubility0.318 mg/mLALOGPS
logP2.94ALOGPS
logP2.62ChemAxon
logS-2.9ALOGPS
pKa (Strongest Basic)8.88ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count2ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area29.26 Å2ChemAxon
Rotatable Bond Count1ChemAxon
Refractivity77.18 m3·mol-1ChemAxon
Polarizability27.56 Å3ChemAxon
Number of Rings3ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleYesChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+1.0
Blood Brain Barrier+0.9837
Caco-2 permeable+0.7206
P-glycoprotein substrateSubstrate0.5814
P-glycoprotein inhibitor INon-inhibitor0.8827
P-glycoprotein inhibitor IINon-inhibitor0.6448
Renal organic cation transporterNon-inhibitor0.5406
CYP450 2C9 substrateNon-substrate0.8614
CYP450 2D6 substrateNon-substrate0.545
CYP450 3A4 substrateNon-substrate0.5637
CYP450 1A2 substrateInhibitor0.9106
CYP450 2C9 inhibitorNon-inhibitor0.9404
CYP450 2D6 inhibitorInhibitor0.8932
CYP450 2C19 inhibitorNon-inhibitor0.9026
CYP450 3A4 inhibitorNon-inhibitor0.8309
CYP450 inhibitory promiscuityHigh CYP Inhibitory Promiscuity0.6612
Ames testNon AMES toxic0.9133
CarcinogenicityNon-carcinogens0.9183
BiodegradationNot ready biodegradable0.9692
Rat acute toxicity2.9821 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Weak inhibitor0.9534
hERG inhibition (predictor II)Inhibitor0.7539
ADMET data is predicted using admetSAR, a free tool for evaluating chemical ADMET properties. (23092397)

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSNot Available
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSNot Available

Taxonomy

Description
This compound belongs to the class of organic compounds known as 4-phenyltetrahydroisoquinolines. These are compounds containing a phenyl group attached to the C4-atom of a tetrahydroisoquinoline moiety.
Kingdom
Organic compounds
Super Class
Organoheterocyclic compounds
Class
Tetrahydroisoquinolines
Sub Class
4-phenyltetrahydroisoquinolines
Direct Parent
4-phenyltetrahydroisoquinolines
Alternative Parents
Aminoquinolines and derivatives / Aralkylamines / Benzene and substituted derivatives / Trialkylamines / Azacyclic compounds / Primary amines / Organopnictogen compounds / Hydrocarbon derivatives
Substituents
4-phenyltetrahydroisoquinoline / Aminoquinoline / Aralkylamine / Benzenoid / Monocyclic benzene moiety / Tertiary aliphatic amine / Tertiary amine / Azacycle / Organic nitrogen compound / Organopnictogen compound
Molecular Framework
Aromatic heteropolycyclic compounds
External Descriptors
isoquinolines (CHEBI:116225)

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Norepinephrine:sodium symporter activity
Specific Function
Amine transporter. Terminates the action of noradrenaline by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name
SLC6A2
Uniprot ID
P23975
Uniprot Name
Sodium-dependent noradrenaline transporter
Molecular Weight
69331.42 Da
References
  1. Tatsumi M, Groshan K, Blakely RD, Richelson E: Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58. [PubMed:9537821]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Monoamine transmembrane transporter activity
Specific Function
Amine transporter. Terminates the action of dopamine by its high affinity sodium-dependent reuptake into presynaptic terminals.
Gene Name
SLC6A3
Uniprot ID
Q01959
Uniprot Name
Sodium-dependent dopamine transporter
Molecular Weight
68494.255 Da
References
  1. Tatsumi M, Groshan K, Blakely RD, Richelson E: Pharmacological profile of antidepressants and related compounds at human monoamine transporters. Eur J Pharmacol. 1997 Dec 11;340(2-3):249-58. [PubMed:9537821]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Primary amine oxidase activity
Specific Function
Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral...
Gene Name
MAOB
Uniprot ID
P27338
Uniprot Name
Amine oxidase [flavin-containing] B
Molecular Weight
58762.475 Da
References
  1. Egashira T, Takayama F, Yamanaka Y: The inhibition of monoamine oxidase activity by various antidepressants: differences found in various mammalian species. Jpn J Pharmacol. 1999 Sep;81(1):115-21. [PubMed:10580379]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Serotonin binding
Specific Function
Catalyzes the oxidative deamination of biogenic and xenobiotic amines and has important functions in the metabolism of neuroactive and vasoactive amines in the central nervous system and peripheral...
Gene Name
MAOA
Uniprot ID
P21397
Uniprot Name
Amine oxidase [flavin-containing] A
Molecular Weight
59681.27 Da
References
  1. Egashira T, Takayama F, Yamanaka Y: The inhibition of monoamine oxidase activity by various antidepressants: differences found in various mammalian species. Jpn J Pharmacol. 1999 Sep;81(1):115-21. [PubMed:10580379]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Peroxidase activity
Specific Function
Part of the host defense system of polymorphonuclear leukocytes. It is responsible for microbicidal activity against a wide range of organisms. In the stimulated PMN, MPO catalyzes the production o...
Gene Name
MPO
Uniprot ID
P05164
Uniprot Name
Myeloperoxidase
Molecular Weight
83867.71 Da
References
  1. Obach RS, Dalvie DK: Metabolism of nomifensine to a dihydroisoquinolinium ion metabolite by human myeloperoxidase, hemoglobin, monoamine oxidase A, and cytochrome P450 enzymes. Drug Metab Dispos. 2006 Aug;34(8):1310-6. Epub 2006 May 5. [PubMed:16679384]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Serotonin:sodium symporter activity
Specific Function
Serotonin transporter whose primary function in the central nervous system involves the regulation of serotonergic signaling via transport of serotonin molecules from the synaptic cleft back into t...
Gene Name
SLC6A4
Uniprot ID
P31645
Uniprot Name
Sodium-dependent serotonin transporter
Molecular Weight
70324.165 Da
References
  1. Henry LK, Field JR, Adkins EM, Parnas ML, Vaughan RA, Zou MF, Newman AH, Blakely RD: Tyr-95 and Ile-172 in transmembrane segments 1 and 3 of human serotonin transporters interact to establish high affinity recognition of antidepressants. J Biol Chem. 2006 Jan 27;281(4):2012-23. Epub 2005 Nov 3. [PubMed:16272152]
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Monoamine transmembrane transporter activity
Specific Function
Involved in the ATP-dependent vesicular transport of biogenic amine neurotransmitters. Pumps cytosolic monoamines including dopamine, norepinephrine, serotonin, and histamine into synaptic vesicles...
Gene Name
SLC18A2
Uniprot ID
Q05940
Uniprot Name
Synaptic vesicular amine transporter
Molecular Weight
55712.075 Da
References
  1. Gonzalez AM, Walther D, Pazos A, Uhl GR: Synaptic vesicular monoamine transporter expression: distribution and pharmacologic profile. Brain Res Mol Brain Res. 1994 Mar;22(1-4):219-26. [PubMed:7912402]

Carriers

Kind
Protein
Organism
Human
Pharmacological action
No
General Function
Not Available
Specific Function
Functions as transport protein in the blood stream. Binds various ligands in the interior of its beta-barrel domain. Also binds synthetic drugs and influences their distribution and availability in...
Gene Name
ORM1
Uniprot ID
P02763
Uniprot Name
Alpha-1-acid glycoprotein 1
Molecular Weight
23511.38 Da
References
  1. Ferry DG, Caplan NB, Cubeddu LX: Interaction between antidepressants and alpha 1-adrenergic receptor antagonists on the binding to alpha 1-acid glycoprotein. J Pharm Sci. 1986 Feb;75(2):146-9. [PubMed:2870173]

Drug created on September 11, 2007 14:22 / Updated on December 01, 2017 15:33