Identification

Name
Nonivamide
Accession Number
DB11324
Type
Small Molecule
Groups
Investigational
Description

Nonivamide is found in herbs and spices. It is an alkaloid from the Capsicum species. The structures of Capsaicin and nonivamide differ only slightly with respect to the fatty acid moiety of the side chain (8-methyl nonenoic acid versus nonanoic acid) [15].

Nonivamide is a flavoring ingredient. Nonivamide is an organic compound and a capsaicinoid. It is an amide of pelargonic acid and vanillylamine. It is present in chili peppers, but is commonly manufactured synthetically. It is more heat-stable than capsaicin [11].

This drug has been studied in combination with Nicarboxil in the treatment of lower back pain [12].

Nonivamide has also been studied for its anti-inflammatory properties, as well as in fat loss therapies and has demonstrated promising results [13], [8], [4], [2].

Structure
Thumb
Synonyms
  • Hydroxymethoxybenzyl pelargonamide
  • N-Nonanoyl vanillylamide
  • N-Vanillylnonamide
  • N-Vanillylpelargonamide
  • Nonivamide
  • Pelargonyl vanillylamide
  • Pseudocapsaicin
  • Vanillyl-N-nonylamide
External IDs
AH-23491X / FEMA NO. 2787 / NSC-172795
Mixture Products
NameIngredientsDosageRouteLabellerMarketing StartMarketing End
Antiphlamine Coin PlasterNonivamide (0.046 mg/0.2832g) + DL-alpha-Tocopherol (0.308 mg/0.2832g) + Diphenhydramine (0.246 mg/0.2832g) + Levomenthol (2.769 mg/0.2832g) + Methyl salicylate (5.541 mg/0.2832g) + Peppermint oil (0.693 mg/0.2832g) + Synthetic Camphor (1.108 mg/0.2832g)PatchTopicalHanul Trading Co., Ltd.2016-10-10Not applicableUs
Family Care Thera FlexNonivamide (.01 mg/100mg) + Glycol salicylate (4.66 mg/100mg) + Levomenthol (6.53 mg/100mg) + alpha-Tocopherol acetate (.93 mg/100mg)PatchTopicalUnited Exchange Corporation2013-11-15Not applicableUs
Categories
UNII
S846B891OR
CAS number
2444-46-4
Weight
Average: 293.4012
Monoisotopic: 293.199093735
Chemical Formula
C17H27NO3
InChI Key
RGOVYLWUIBMPGK-UHFFFAOYSA-N
InChI
InChI=1S/C17H27NO3/c1-3-4-5-6-7-8-9-17(20)18-13-14-10-11-15(19)16(12-14)21-2/h10-12,19H,3-9,13H2,1-2H3,(H,18,20)
IUPAC Name
N-[(4-hydroxy-3-methoxyphenyl)methyl]nonanamide
SMILES
CCCCCCCCC(=O)NCC1=CC(OC)=C(O)C=C1

Pharmacology

Indication

Nonivamide is used as a topical analgesic and is also used as a flavoring ingredient [11], [2], [12].

Pharmacodynamics

Relieves minor aches and pains of muscles and joints [11], [12].

Mechanism of action

Nonivamide is a naturally occurring analog of Capsaicin, isolated from peppers, described to produce effects similar to Capsaicin. It is an agonist of the VR1 (vanilloid/TRPV1 receptor) [10]. It serves as a transient agonist of these receptors, which are potentiated by pro-inflammatory drugs, a phenomenon that leads to thermal hyperalgesia, or increased heat sensation [9].

Nonivamide has been shown to stimulate afferent neurons with about half the potency of Capsaicin. Agonism of the VR1 (TRPV1) (vanilloid) receptor by Nonivamide was demonstrated to induce the release of Ca2+ from the endoplasmic reticulum (ER) of human lung cells, producing ER stress and cell death [MSDS].

Nonivamide, like other capsaicinoids, acts on the vanilloid receptors located in the peripheral afferent nerve fibers, providing short-acting irritant and algesic properties. Applied dermally, these substances act by stimulating sensitive chemoreceptors of the skin and by reflex, hyperemia and a local elevation in temperature. After repetitive administration, capsaicinoids have been reported to lead to desensitization to nociceptive stimuli possibly by long-acting depletion of peptide neurotransmitters (substance P) from peripheral sensory neurons. Capsaicinoids can modulate muscle tone (in bladder, bronchus etc.). Intravenous injection of nonivamide to rats (10 μg/kg) has been found to lead to bradycardia. The cardiovascular effects are partly explained by substance P release. Nonivamide given to rats subcutaneously (1 mg/kg) was found to cause body temperature decrease, vasodilatation, and increased salivation. Capsaicinoids have shown to illicit bronchospastic effects in guinea pigs. Capsaicin and its analogs were reported to increase barbiturate sleeping time in rats by interacting with hepatic metabolizing enzymes [15].

TargetActionsOrganism
ATransient receptor potential cation channel subfamily V member 1
agonist
Humans
Absorption
Not Available
Volume of distribution
Not Available
Protein binding
Not Available
Metabolism

Limited information is available on pharmacokinetics and metabolism of nonivamide [15]. For the closely related Capsaicin and other capsaicinoids, gastrointestinal absorption is rapid and almost entirely complete in studies of rats (oral dose of about 10 to 15 mg/kg of combined capsaicin and dihydrocapsaicin) with about 85% of the dose being absorbed within 3 hours. Both substances undergo first-pass metabolism in the liver and partly metabolized at the site of absorption [15].

Route of elimination
Not Available
Half life

About 7 minutes [15].

Clearance
Not Available
Toxicity

Nonivamide appears to be of low acute toxicity, according to the EMA summary report [15]. The oral LD50 in rats is reported with 5110 mg/kg and the dermal LD50 in rabbits is greater than 10 000 mg/kg. Administered intraperitoneally, the LD50 in rats was measured to be about 90 mg/kg. In combination with nicoboxil, the acute dermal toxicity of nonivamide was increased. Signs of toxicity (depression, labored respiration, diarrhea) were observed at doses as low as 32 mg/kg body weight of nonivamide combined 200 mg nicoboxil/kg body weight [15].

Allergic reactions in humans following administration of capsaicin or capsicum extracts are reported to be rare [15].

No information on carcinogenic properties of nonivamide was available. Tumorigenic properties have been reported in literature for Capsaicin or chili [15].

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

Interactions

Drug Interactions
Not Available
Food Interactions
Not Available

References

General References
  1. Rohm B, Holik AK, Somoza MM, Pignitter M, Zaunschirm M, Ley JP, Krammer GE, Somoza V: Nonivamide, a capsaicin analog, increases dopamine and serotonin release in SH-SY5Y cells via a TRPV1-independent pathway. Mol Nutr Food Res. 2013 Nov;57(11):2008-18. doi: 10.1002/mnfr.201200846. Epub 2013 Aug 9. [PubMed:23929722]
  2. Walker J, Ley JP, Schwerzler J, Lieder B, Beltran L, Ziemba PM, Hatt H, Hans J, Widder S, Krammer GE, Somoza V: Nonivamide, a capsaicin analogue, exhibits anti-inflammatory properties in peripheral blood mononuclear cells and U-937 macrophages. Mol Nutr Food Res. 2017 Feb;61(2). doi: 10.1002/mnfr.201600474. Epub 2016 Nov 15. [PubMed:27666931]
  3. Hochkogler CM, Rohm B, Hojdar K, Pignitter M, Widder S, Ley JP, Krammer GE, Somoza V: The capsaicin analog nonivamide decreases total energy intake from a standardized breakfast and enhances plasma serotonin levels in moderately overweight men after administered in an oral glucose tolerance test: a randomized, crossover trial. Mol Nutr Food Res. 2014 Jun;58(6):1282-90. doi: 10.1002/mnfr.201300821. Epub 2014 Feb 7. [PubMed:24753478]
  4. Rohm B, Riedel A, Ley JP, Widder S, Krammer GE, Somoza V: Capsaicin, nonivamide and trans-pellitorine decrease free fatty acid uptake without TRPV1 activation and increase acetyl-coenzyme A synthetase activity in Caco-2 cells. Food Funct. 2015 Jan;6(1):173-85. doi: 10.1039/c4fo00435c. Epub 2014 Nov 25. [PubMed:25422952]
  5. Gaubitz M, Schiffer T, Holm C, Richter E, Pisternick-Ruf W, Weiser T: Efficacy and safety of nicoboxil/nonivamide ointment for the treatment of acute pain in the low back - A randomized, controlled trial. Eur J Pain. 2016 Feb;20(2):263-73. doi: 10.1002/ejp.719. Epub 2015 Apr 30. [PubMed:25929250]
  6. Blahova Z, Holm JC, Weiser T, Richter E, Trampisch M, Akarachkova E: Nicoboxil/nonivamide cream effectively and safely reduces acute nonspecific low back pain - a randomized, placebo-controlled trial. J Pain Res. 2016 Dec 14;9:1221-1230. doi: 10.2147/JPR.S118329. eCollection 2016. [PubMed:28008281]
  7. Skofitsch G, Donnerer J, Lembeck F: Comparison of nonivamide and capsaicin with regard to their pharmacokinetics and effects on sensory neurons. Arzneimittelforschung. 1984;34(2):154-6. [PubMed:6202305]
  8. Hochkogler CM, Lieder B, Rust P, Berry D, Meier SM, Pignitter M, Riva A, Leitinger A, Bruk A, Wagner S, Hans J, Widder S, Ley JP, Krammer GE, Somoza V: A 12-week intervention with nonivamide, a TRPV1 agonist, prevents a dietary-induced body fat gain and increases peripheral serotonin in moderately overweight subjects. Mol Nutr Food Res. 2017 May;61(5). doi: 10.1002/mnfr.201600731. Epub 2017 Feb 22. [PubMed:28012242]
  9. Rollyson WD, Stover CA, Brown KC, Perry HE, Stevenson CD, McNees CA, Ball JG, Valentovic MA, Dasgupta P: Bioavailability of capsaicin and its implications for drug delivery. J Control Release. 2014 Dec 28;196:96-105. doi: 10.1016/j.jconrel.2014.09.027. Epub 2014 Oct 12. [PubMed:25307998]
  10. Messeguer A, Planells-Cases R, Ferrer-Montiel A: Physiology and pharmacology of the vanilloid receptor. Curr Neuropharmacol. 2006 Jan;4(1):1-15. [PubMed:18615132]
  11. Nonivamine [Link]
  12. Nonivamide/Nicoboxil Ointment in Acute Low Back Pain [Link]
  13. Capsaicin and nonivamide similarly modulate outcome measures of mitochondrial energy metabolism in HepG2 and 3T3-L1 cells [Link]
  14. Nonivamide, a capsaicin analog, increases dopamine and serotonin release in SH‐SY5Y cells via a TRPV1‐independent pathway [Link]
  15. EMA summary report Nonivamide [File]
External Links
Human Metabolome Database
HMDB0029846
ChemSpider
2891
BindingDB
50044767
ChEBI
46936
ChEMBL
CHEMBL75124
Wikipedia
Nonivamide
MSDS
Download (390 KB)

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
3CompletedTreatmentAcute Low Back Pain1
3CompletedTreatmentBack Pain Lower Back1

Pharmacoeconomics

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

Properties

State
Not Available
Experimental Properties
PropertyValueSource
melting point (°C)57MSDS
boiling point (°C)492.7MSDS
water solubilitySoluble in water (slightly)MSDS
pKa9.77MSDS
Predicted Properties
PropertyValueSource
Water Solubility0.0233 mg/mLALOGPS
logP4.05ALOGPS
logP3.82ChemAxon
logS-4.1ALOGPS
pKa (Strongest Acidic)9.93ChemAxon
pKa (Strongest Basic)-0.52ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count3ChemAxon
Hydrogen Donor Count2ChemAxon
Polar Surface Area58.56 Å2ChemAxon
Rotatable Bond Count10ChemAxon
Refractivity84.65 m3·mol-1ChemAxon
Polarizability35.07 Å3ChemAxon
Number of Rings1ChemAxon
Bioavailability1ChemAxon
Rule of FiveYesChemAxon
Ghose FilterYesChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleNoChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
SpectrumSpectrum TypeSplash Key
Predicted GC-MS Spectrum - GC-MSPredicted GC-MSNot Available
GC-MS Spectrum - EI-BGC-MSsplash10-000i-0900000000-6f2029bbeaa0669340a0
Predicted MS/MS Spectrum - 10V, Positive (Annotated)Predicted LC-MS/MSsplash10-0006-0950000000-67e561ae29f2afb29778
Predicted MS/MS Spectrum - 20V, Positive (Annotated)Predicted LC-MS/MSsplash10-000i-1900000000-22d461bcbb8449562ea6
Predicted MS/MS Spectrum - 40V, Positive (Annotated)Predicted LC-MS/MSsplash10-000i-5900000000-0d2b494b9af632d043d1
Predicted MS/MS Spectrum - 10V, Negative (Annotated)Predicted LC-MS/MSsplash10-0006-0390000000-ec9c31843d3afbcd0939
Predicted MS/MS Spectrum - 20V, Negative (Annotated)Predicted LC-MS/MSsplash10-0k9f-0940000000-709a4f4d48c16fcf8747
Predicted MS/MS Spectrum - 40V, Negative (Annotated)Predicted LC-MS/MSsplash10-052o-7900000000-f49d6bc681a0fe7bb4ac
MS/MS Spectrum - , positiveLC-MS/MSsplash10-000i-3900000000-0e1c18bae04636c6203e
LC-MS/MS Spectrum - LC-ESI-QFT , positiveLC-MS/MSsplash10-000i-0900000000-8458eb835ff534a3139b
1H NMR Spectrum1D NMRNot Applicable
13C NMR Spectrum1D NMRNot Applicable

Taxonomy

Description
This compound belongs to the class of organic compounds known as methoxyphenols. These are compounds containing a methoxy group attached to the benzene ring of a phenol moiety.
Kingdom
Organic compounds
Super Class
Benzenoids
Class
Phenols
Sub Class
Methoxyphenols
Direct Parent
Methoxyphenols
Alternative Parents
Phenoxy compounds / Methoxybenzenes / Anisoles / Alkyl aryl ethers / 1-hydroxy-2-unsubstituted benzenoids / Propargyl-type 1,3-dipolar organic compounds / Carboximidic acids / Organopnictogen compounds / Organonitrogen compounds / Hydrocarbon derivatives
Substituents
Methoxyphenol / Phenoxy compound / Anisole / Methoxybenzene / Phenol ether / Alkyl aryl ether / 1-hydroxy-2-unsubstituted benzenoid / Monocyclic benzene moiety / Carboximidic acid / Carboximidic acid derivative
Molecular Framework
Aromatic homomonocyclic compounds
External Descriptors
phenols, capsaicinoid (CHEBI:46936) / an alkaloid (CPD-9183)

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
General Function
Transmembrane signaling receptor activity
Specific Function
Ligand-activated non-selective calcium permeant cation channel involved in detection of noxious chemical and thermal stimuli. Seems to mediate proton influx and may be involved in intracellular aci...
Gene Name
TRPV1
Uniprot ID
Q8NER1
Uniprot Name
Transient receptor potential cation channel subfamily V member 1
Molecular Weight
94955.33 Da
References
  1. Thomas KC, Ethirajan M, Shahrokh K, Sun H, Lee J, Cheatham TE 3rd, Yost GS, Reilly CA: Structure-activity relationship of capsaicin analogs and transient receptor potential vanilloid 1-mediated human lung epithelial cell toxicity. J Pharmacol Exp Ther. 2011 May;337(2):400-10. doi: 10.1124/jpet.110.178491. Epub 2011 Feb 22. [PubMed:21343315]
  2. Skofitsch G, Donnerer J, Lembeck F: Comparison of nonivamide and capsaicin with regard to their pharmacokinetics and effects on sensory neurons. Arzneimittelforschung. 1984;34(2):154-6. [PubMed:6202305]
  3. Rohm B, Holik AK, Somoza MM, Pignitter M, Zaunschirm M, Ley JP, Krammer GE, Somoza V: Nonivamide, a capsaicin analog, increases dopamine and serotonin release in SH-SY5Y cells via a TRPV1-independent pathway. Mol Nutr Food Res. 2013 Nov;57(11):2008-18. doi: 10.1002/mnfr.201200846. Epub 2013 Aug 9. [PubMed:23929722]

Drug created on December 03, 2015 09:52 / Updated on December 16, 2018 06:58