Identification

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Name
Loxicodegol
Accession Number
DB14146
Type
Small Molecule
Groups
Investigational
Description

Loxicodegol was developed by Nektar Therapeutics as an opioid analgesic with low abuse potential for the treatment of chronic pain 4. The lack of abuse potential is believed to be due to the drug's slow rate of entry into brain, a unique characteristic compared to others in the opioid class 1,2. This is also thought to be the reason behind the reduced frequency of CNS-mediated adverse effects, like sedation, seen with Loxicodegol. Nektar Therapeutics has filed an application for FDA approval of Loxicodegol for use in the treatment of chronic lower back pain 4

Structure
Thumb
Synonyms
Not Available
External IDs
NKTR 181 / NKTR-181
Categories
Not Available
UNII
J2WIV0JMML
CAS number
1211231-76-3
Weight
Average: 595.73
Monoisotopic: 595.335646782
Chemical Formula
C31H49NO10
InChI Key
RQHILGKAOIGUHU-XPLSERNMSA-N
InChI
InChI=1S/C31H49NO10/c1-32-9-8-30-27-23-4-5-24(35-3)28(27)42-29(30)25(6-7-31(30,33)26(32)22-23)41-21-20-40-19-18-39-17-16-38-15-14-37-13-12-36-11-10-34-2/h4-5,25-26,29,33H,6-22H2,1-3H3/t25-,26+,29-,30-,31+/m0/s1
IUPAC Name
(1S,5R,13R,14S,17S)-14-(2,5,8,11,14,17-hexaoxanonadecan-19-yloxy)-10-methoxy-4-methyl-12-oxa-4-azapentacyclo[9.6.1.0^{1,13}.0^{5,17}.0^{7,18}]octadeca-7(18),8,10-trien-17-ol
SMILES
[H][C@@]12OC3=C(OC)C=CC4=C3[C@@]11CCN(C)[C@]([H])(C4)[C@]1(O)CC[C@]2([H])OCCOCCOCCOCCOCCOCCOC

Pharmacology

Indication

Loxicodegol was developed as an opioid analgesic with low abuse potential for use in treating chronic pain 4. An application has been filed for FDA approval of Loxicodegol for use in treating chronic lower back pain.

Pharmacodynamics

Loxicodegol displays full analgesic activity comparable to that of oxycodone, producing similar acetone-writhing test responses in mice and hot-plate test maximal latencies in rats 2.

The safety profile of Loxicodegol is much improved from that of other opioid analgesics 1. The incidence of respiratory depression and sedation is reduced compared to oxycodone and morphine. Generalized pruritus occurred in 7.3% and 4.9% of subjects at 200mg and 400mg of Loxicodegol compared to 41.5% with 40mg oxycodone. Nausea occurred in 2.5%, 2.4%, and 7.3% with 100mg, 200mg, and 400mg of Loxecodegol compared to 29.3% with 40mg oxycodone. Lastly, vomiting occurred in 2.4% with both 200mg and 400mg Loxicodegol compared to 24.4% with 40mg oxycodone.

Loxicodegol is much less addictive than other opioid analgesics. It produces a only a slight high at dosages of 400mg, peaking at scores only 25% that of oxycodone, with no difference compared to placebo at lower dosages. No differences have been noted between Loxicodegol and saline in self-administration or behavior reinforcement in monkeys or rats 1,2

Mechanism of action

Loxicodegol is a full agonist at the μ-opioid receptor. It also displays selectivity towards this subtype with an affinity of 237 nM compared to 4150 nM and >100000 nM for the δ- and κ-opioid receptors. The μ-opioid receptor is activated with an EC₅₀ of 12.5 μM. Activation of this receptor produces an inhibitory effect on neurotransmission through Gi/Go coupling 3. Opioid medications like Loxicodegol inhibit voltage gated Ca²⁺ channel opening presynaptically on C fibres and activate inward-rectifying K⁺ channels post-synaptically on 2nd order neurons, leading to hyperpolarization. Together, these prevent the nociceptive signal from traveling up the spinal cord to the brain. In the brain, opioids work through a mechanism of inhibition of inhibition to allow regulatory neurons to suppress nociception.

TargetActionsOrganism
AMu-type opioid receptor
agonist
Humans
UDelta-type opioid receptor
agonist
Humans
UKappa-type opioid receptor
agonist
Humans
Absorption

Loxicodegol has a Tmax of 1.8h and a bioavailability of 34% with oral administration 2. It enters the brain about 17-70 times more slowly than oxycodone 1. Loxicodegol is also a p-glycoprotein substrate further reducing its transport into the brain.

Volume of distribution

Loxicodegol has a steady-state Vd of 4.19 L/kg 2.

Protein binding
Not Available
Metabolism
Not Available
Route of elimination
Not Available
Half life

Loxicodegol has a half-life of 4.53 h allowing for a longer duration of action 2.

Clearance

Loxicodegol has a clearance rate of 59.3 mL/min/kg 2.

Toxicity
Not Available
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. Webster L, Henningfield J, Buchhalter AR, Siddhanti S, Lu L, Odinecs A, Di Fonzo CJ, Eldon MA: Human Abuse Potential of the New Opioid Analgesic Molecule NKTR-181 Compared with Oxycodone. Pain Med. 2018 Feb 1;19(2):307-318. doi: 10.1093/pm/pnw344. [PubMed:28340145]
  2. Miyazaki T, Choi IY, Rubas W, Anand NK, Ali C, Evans J, Gursahani H, Hennessy M, Kim G, McWeeney D, Pfeiffer J, Quach P, Gauvin D, Riley TA, Riggs JA, Gogas K, Zalevsky J, Doberstein SK: NKTR-181: A Novel Mu-Opioid Analgesic with Inherently Low Abuse Potential. J Pharmacol Exp Ther. 2017 Oct;363(1):104-113. doi: 10.1124/jpet.117.243030. Epub 2017 Aug 4. [PubMed:28778859]
  3. Goodman, Louis Sanford;Brunton, Laurence L.;Chabner, Bruce;Knollman, Bjorn (2011). The Pharmacological Basis of Therapeutics (12th ed.). McGraw-Hill Professional Publishing. [ISBN:978-0-07-162442-8]
  4. Nektar Therapeutics: Loxicodegol FDA Application Press Release [Link]
External Links
ChemSpider
64854462

Clinical Trials

Clinical Trials
PhaseStatusPurposeConditionsCount
1RecruitingBasic ScienceBack Pain Lower Back Chronic1
2CompletedTreatmentKnee Osteoarthritis (Knee OA)1
3CompletedTreatmentBack Pain Lower Back / Pain, Chronic2

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 Solubility0.0487 mg/mLALOGPS
logP1.34ALOGPS
logP0.98ChemAxon
logS-4.1ALOGPS
pKa (Strongest Acidic)13.58ChemAxon
pKa (Strongest Basic)8.92ChemAxon
Physiological Charge1ChemAxon
Hydrogen Acceptor Count11ChemAxon
Hydrogen Donor Count1ChemAxon
Polar Surface Area106.54 Å2ChemAxon
Rotatable Bond Count20ChemAxon
Refractivity155.95 m3·mol-1ChemAxon
Polarizability66.68 Å3ChemAxon
Number of Rings5ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Predicted ADMET features
Not Available

Spectra

Mass Spec (NIST)
Not Available
Spectra
Not Available

Taxonomy

Classification
Not classified

Targets

Kind
Protein
Organism
Humans
Pharmacological action
Yes
Actions
Agonist
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
References
  1. Miyazaki T, Choi IY, Rubas W, Anand NK, Ali C, Evans J, Gursahani H, Hennessy M, Kim G, McWeeney D, Pfeiffer J, Quach P, Gauvin D, Riley TA, Riggs JA, Gogas K, Zalevsky J, Doberstein SK: NKTR-181: A Novel Mu-Opioid Analgesic with Inherently Low Abuse Potential. J Pharmacol Exp Ther. 2017 Oct;363(1):104-113. doi: 10.1124/jpet.117.243030. Epub 2017 Aug 4. [PubMed:28778859]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
Curator comments
While Loxicodegol binds to this receptor at higher concentrations, it does not produce an appreciable effect.
General Function
Opioid receptor activity
Specific Function
G-protein coupled receptor that functions as receptor for endogenous enkephalins and for a subset of other opioids. Ligand binding causes a conformation change that triggers signaling via guanine n...
Gene Name
OPRD1
Uniprot ID
P41143
Uniprot Name
Delta-type opioid receptor
Molecular Weight
40368.235 Da
References
  1. Miyazaki T, Choi IY, Rubas W, Anand NK, Ali C, Evans J, Gursahani H, Hennessy M, Kim G, McWeeney D, Pfeiffer J, Quach P, Gauvin D, Riley TA, Riggs JA, Gogas K, Zalevsky J, Doberstein SK: NKTR-181: A Novel Mu-Opioid Analgesic with Inherently Low Abuse Potential. J Pharmacol Exp Ther. 2017 Oct;363(1):104-113. doi: 10.1124/jpet.117.243030. Epub 2017 Aug 4. [PubMed:28778859]
Kind
Protein
Organism
Humans
Pharmacological action
Unknown
Actions
Agonist
Curator comments
While Loxicodegol binds to this receptor at higher concentrations, it does not produce an appreciable effect.
General Function
Opioid receptor activity
Specific Function
G-protein coupled opioid receptor that functions as receptor for endogenous alpha-neoendorphins and dynorphins, but has low affinity for beta-endorphins. Also functions as receptor for various synt...
Gene Name
OPRK1
Uniprot ID
P41145
Uniprot Name
Kappa-type opioid receptor
Molecular Weight
42644.665 Da
References
  1. Miyazaki T, Choi IY, Rubas W, Anand NK, Ali C, Evans J, Gursahani H, Hennessy M, Kim G, McWeeney D, Pfeiffer J, Quach P, Gauvin D, Riley TA, Riggs JA, Gogas K, Zalevsky J, Doberstein SK: NKTR-181: A Novel Mu-Opioid Analgesic with Inherently Low Abuse Potential. J Pharmacol Exp Ther. 2017 Oct;363(1):104-113. doi: 10.1124/jpet.117.243030. Epub 2017 Aug 4. [PubMed:28778859]

Transporters

Kind
Protein
Organism
Humans
Pharmacological action
Unknown
General Function
Xenobiotic-transporting atpase activity
Specific Function
Energy-dependent efflux pump responsible for decreased drug accumulation in multidrug-resistant cells.
Gene Name
ABCB1
Uniprot ID
P08183
Uniprot Name
Multidrug resistance protein 1
Molecular Weight
141477.255 Da
References
  1. Webster L, Henningfield J, Buchhalter AR, Siddhanti S, Lu L, Odinecs A, Di Fonzo CJ, Eldon MA: Human Abuse Potential of the New Opioid Analgesic Molecule NKTR-181 Compared with Oxycodone. Pain Med. 2018 Feb 1;19(2):307-318. doi: 10.1093/pm/pnw344. [PubMed:28340145]

Drug created on June 28, 2018 08:58 / Updated on May 01, 2019 11:57