Epicept NP-1

Identification

Name
Epicept NP-1
Accession Number
DB05492  (DB08290)
Type
Small Molecule
Groups
Investigational
Description

EpiCept NP-1 is a prescription topical analgesic cream designed to provide effective, long-term relief from the pain of peripheral neuropathies. Peripheral neuropathies are medical conditions caused by damage to the nerves in the peripheral nervous system. The peripheral nervous system includes nerves that run from the brain and spinal cord to the rest of the body. EpiCept NP-1 Cream is a patented formulation containing two FDA-approved drugs, amitriptyline (a widely-used antidepressant) and ketamine (an NMDA antagonist that is used as an anesthetic).

Structure
Thumb
Synonyms
Not Available
Categories
Not Available
UNII
Not Available
CAS number
Not Available
Weight
Average: 209.245
Monoisotopic: 209.116426739
Chemical Formula
C10H15N3O2
InChI Key
FKZUPMCBVURANR-UHFFFAOYSA-N
InChI
InChI=1S/C10H15N3O2/c1-8-3-4-9(12-6-2-5-11)10(7-8)13(14)15/h3-4,7,12H,2,5-6,11H2,1H3
IUPAC Name
N1-(4-methyl-2-nitrophenyl)propane-1,3-diamine
SMILES
CC1=CC(=C(NCCCN)C=C1)[N+]([O-])=O

Pharmacology

Indication

Investigated for use/treatment in neuropathy (diabetic) and pain (acute or chronic).

Pharmacodynamics

EpiCept NP-1 is a prescription topical analgesic cream designed to provide effective, long-term relief from the pain of peripheral neuropathies. Peripheral neuropathies are medical conditions caused by damage to the nerves in the peripheral nervous system. The peripheral nervous system includes nerves that run from the brain and spinal cord to the rest of the body. It is estimated that these conditions affect more than 15 million people in the U.S. and is associated with conditions that injure peripheral nerves, including herpes zoster, or shingles, diabetes, chemotherapy, HIV and other diseases. Peripheral neuropathies can also be caused by trauma or may result from surgical procedures. EpiCept NP-1 Cream is a patented formulation containing two FDA-approved drugs, amitriptyline (a widely-used antidepressant) and ketamine (an NMDA antagonist that is used as an anesthetic).

Mechanism of action

The mechanism(s) of action are unclear for Epicept. Both ketamine and amitriptyline inhibit N-methyl-D-aspartate receptors in neuronal preparations and may be involved in sensitization of tetrodotoxin-resistant Na+ currents in nociceptors by blocking Na+ channels. In producing antihyperalgesia with pretreatment, but not posttreatment, regimens, ketamine and amitriptyline resemble the profile of a µ-opioid receptor agonist. In addition to the above effects, amitriptyline also inhibits noradrenaline, 5-HT, and adenosine uptake; inter-acts with opioid mechanisms; blocks Ca2+ channels; and blocks cholinergic, histamine H1, 5-HT2, and {alpha}-adrenergic receptors. Accordingly there are many possible mechanisms at work.

TargetActionsOrganism
UMu-type opioid receptorNot AvailableHuman
U5-hydroxytryptamine receptor 2ANot AvailableHuman
U5-hydroxytryptamine receptor 2BNot AvailableHuman
U5-hydroxytryptamine receptor 2CNot AvailableHuman
UAlpha-1A adrenergic receptorNot AvailableHuman
UAlpha-1B adrenergic receptorNot AvailableHuman
UAlpha-1D adrenergic receptorNot AvailableHuman
UAlpha-2A adrenergic receptorNot AvailableHuman
UAlpha-2B adrenergic receptorNot AvailableHuman
UAlpha-2C adrenergic receptorNot AvailableHuman
UHistamine H1 receptorNot AvailableHuman
UNociceptin receptorNot 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

Mild sensitivity at application site

Affected organisms
Not Available
Pathways
Not Available
Pharmacogenomic Effects/ADRs
Not Available

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Sandroni P, Davis MD: Combination gel of 1% amitriptyline and 0.5% ketamine to treat refractory erythromelalgia pain: a new treatment option? Arch Dermatol. 2006 Mar;142(3):283-6. [PubMed:16549702]
  2. Lynch ME, Clark AJ, Sawynok J, Sullivan MJ: Topical amitriptyline and ketamine in neuropathic pain syndromes: an open-label study. J Pain. 2005 Oct;6(10):644-9. [PubMed:16202956]
  3. Lynch ME, Clark AJ, Sawynok J, Sullivan MJ: Topical 2% amitriptyline and 1% ketamine in neuropathic pain syndromes: a randomized, double-blind, placebo-controlled trial. Anesthesiology. 2005 Jul;103(1):140-6. [PubMed:15983466]
  4. Oatway M, Reid A, Sawynok J: Peripheral antihyperalgesic and analgesic actions of ketamine and amitriptyline in a model of mild thermal injury in the rat. Anesth Analg. 2003 Jul;97(1):168-73, table of contents. [PubMed:12818961]
External Links
PubChem Compound
5276854
PubChem Substance
175427020
ChemSpider
4440796
BindingDB
50398244
ChEMBL
CHEMBL609728
HET
NP1
PDB Entries
1wug

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
2CompletedTreatmentDiabetic Peripheral Neuropathy (DPN) / Neurocostal neuralgia1
3CompletedSupportive CareNeurotoxicity / Pain / Peripheral Neuropathy / Unspecified Adult Solid Tumor, Protocol Specific1

Pharmacoeconomics

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

Properties

State
Solid
Experimental Properties
Not Available
Predicted Properties
PropertyValueSource
Water Solubility0.472 mg/mLALOGPS
logP1.8ALOGPS
logP1.81ChemAxon
logS-2.6ALOGPS
pKa (Strongest Acidic)13.99ChemAxon
pKa (Strongest Basic)9.82ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count4ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area83.87 Å2ChemAxon
Rotatable Bond Count5ChemAxon
Refractivity61.43 m3·mol-1ChemAxon
Polarizability22.54 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
PropertyValueProbability
Human Intestinal Absorption+0.9629
Blood Brain Barrier+0.787
Caco-2 permeable-0.5109
P-glycoprotein substrateNon-substrate0.5295
P-glycoprotein inhibitor INon-inhibitor0.7583
P-glycoprotein inhibitor IINon-inhibitor0.8837
Renal organic cation transporterNon-inhibitor0.7637
CYP450 2C9 substrateNon-substrate0.8113
CYP450 2D6 substrateNon-substrate0.7816
CYP450 3A4 substrateNon-substrate0.6621
CYP450 1A2 substrateInhibitor0.8305
CYP450 2C9 inhibitorNon-inhibitor0.5367
CYP450 2D6 inhibitorNon-inhibitor0.8092
CYP450 2C19 inhibitorNon-inhibitor0.547
CYP450 3A4 inhibitorNon-inhibitor0.7969
CYP450 inhibitory promiscuityLow CYP Inhibitory Promiscuity0.7156
Ames testAMES toxic0.8628
CarcinogenicityNon-carcinogens0.5464
BiodegradationNot ready biodegradable0.9626
Rat acute toxicity2.4866 LD50, mol/kg Not applicable
hERG inhibition (predictor I)Strong inhibitor0.5324
hERG inhibition (predictor II)Non-inhibitor0.6512
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 GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
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 nitrobenzenes. These are compounds containing a nitrobenzene moiety, which consists of a benzene ring with a carbon bearing a nitro group.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Benzene and substituted derivatives
Sub Class
Nitrobenzenes
Direct Parent
Nitrobenzenes
Alternative Parents
Nitrotoluenes / Phenylalkylamines / Nitroaromatic compounds / Aniline and substituted anilines / Aminotoluenes / Secondary alkylarylamines / Propargyl-type 1,3-dipolar organic compounds / Organic oxoazanium compounds / Organopnictogen compounds / Organic zwitterions
show 3 more
Substituents
Nitrobenzene / Nitrotoluene / Nitroaromatic compound / Aniline or substituted anilines / Aminotoluene / Phenylalkylamine / Secondary aliphatic/aromatic amine / Toluene / C-nitro compound / Organic nitro compound
show 16 more
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
Not Available

Targets

Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Voltage-gated calcium channel activity
Specific Function
Receptor for endogenous opioids such as beta-endorphin and endomorphin. Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone...
Gene Name
OPRM1
Uniprot ID
P35372
Uniprot Name
Mu-type opioid receptor
Molecular Weight
44778.855 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Virus receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including mescaline, psilocybin, 1-(2,5-dimethoxy-4-iodop...
Gene Name
HTR2A
Uniprot ID
P28223
Uniprot Name
5-hydroxytryptamine receptor 2A
Molecular Weight
52602.58 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various ergot alkaloid derivatives and psychoactive substances. Ligand binding causes a conformation...
Gene Name
HTR2B
Uniprot ID
P41595
Uniprot Name
5-hydroxytryptamine receptor 2B
Molecular Weight
54297.41 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Serotonin receptor activity
Specific Function
G-protein coupled receptor for 5-hydroxytryptamine (serotonin). Also functions as a receptor for various drugs and psychoactive substances, including ergot alkaloid derivatives, 1-2,5,-dimethoxy-4-...
Gene Name
HTR2C
Uniprot ID
P28335
Uniprot Name
5-hydroxytryptamine receptor 2C
Molecular Weight
51820.705 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Protein heterodimerization activity
Specific Function
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) prot...
Gene Name
ADRA1A
Uniprot ID
P35348
Uniprot Name
Alpha-1A adrenergic receptor
Molecular Weight
51486.005 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Protein heterodimerization activity
Specific Function
This alpha-adrenergic receptor mediates its action by association with G proteins that activate a phosphatidylinositol-calcium second messenger system. Its effect is mediated by G(q) and G(11) prot...
Gene Name
ADRA1B
Uniprot ID
P35368
Uniprot Name
Alpha-1B adrenergic receptor
Molecular Weight
56835.375 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Alpha1-adrenergic receptor activity
Specific Function
This alpha-adrenergic receptor mediates its effect through the influx of extracellular calcium.
Gene Name
ADRA1D
Uniprot ID
P25100
Uniprot Name
Alpha-1D adrenergic receptor
Molecular Weight
60462.205 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Thioesterase binding
Specific Function
Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is oxymetazo...
Gene Name
ADRA2A
Uniprot ID
P08913
Uniprot Name
Alpha-2A adrenergic receptor
Molecular Weight
48956.275 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Epinephrine binding
Specific Function
Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins. The rank order of potency for agonists of this receptor is clonidine...
Gene Name
ADRA2B
Uniprot ID
P18089
Uniprot Name
Alpha-2B adrenergic receptor
Molecular Weight
49565.8 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Protein homodimerization activity
Specific Function
Alpha-2 adrenergic receptors mediate the catecholamine-induced inhibition of adenylate cyclase through the action of G proteins.
Gene Name
ADRA2C
Uniprot ID
P18825
Uniprot Name
Alpha-2C adrenergic receptor
Molecular Weight
49521.585 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Histamine receptor activity
Specific Function
In peripheral tissues, the H1 subclass of histamine receptors mediates the contraction of smooth muscles, increase in capillary permeability due to contraction of terminal venules, and catecholamin...
Gene Name
HRH1
Uniprot ID
P35367
Uniprot Name
Histamine H1 receptor
Molecular Weight
55783.61 Da
Kind
Protein
Organism
Human
Pharmacological action
Unknown
General Function
Nociceptin receptor activity
Specific Function
G-protein coupled opioid receptor that functions as receptor for the endogenous neuropeptide nociceptin. Ligand binding causes a conformation change that triggers signaling via guanine nucleotide-b...
Gene Name
OPRL1
Uniprot ID
P41146
Uniprot Name
Nociceptin receptor
Molecular Weight
40692.775 Da

Drug created on November 18, 2007 11:25 / Updated on August 02, 2018 05:31