Identification
- Generic Name
- Loxicodegol
- DrugBank Accession Number
- DB14146
- Background
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
- Type
- Small Molecule
- Groups
- Investigational
- Structure
Structure for Loxicodegol (DB14146)
- Weight
- Average: 595.73
Monoisotopic: 595.335646782 - Chemical Formula
- C31H49NO10
- Synonyms
- Not Available
- External IDs
- NKTR 181
- NKTR-181
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.
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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.
Target Actions Organism AMu-type opioid receptor agonistHumans UDelta-type opioid receptor agonistHumans UKappa-type opioid receptor agonistHumans - 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.
- Adverse Effects
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Not Available
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.Not Available
- Food Interactions
- Not Available
Categories
- Drug Categories
- Classification
- Not classified
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- J2WIV0JMML
- CAS number
- 1211231-76-3
- 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
References
- General References
- 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. [Article]
- 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. [Article]
- 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]
- Nektar Therapeutics: Loxicodegol FDA Application Press Release [Link]
- External Links
- ChemSpider
- 64854462
Clinical Trials
- Clinical Trials
Phase Status Purpose Conditions Count 3 Completed Treatment Back Pain Lower Back / Chronic Pain 2 2 Completed Treatment Osteoarthritis of the Knee 1 1 Terminated Basic Science Moderate to Severe Chronic Pain 1
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
Property Value Source Water Solubility 0.0487 mg/mL ALOGPS logP 1.34 ALOGPS logP 0.98 Chemaxon logS -4.1 ALOGPS pKa (Strongest Acidic) 13.58 Chemaxon pKa (Strongest Basic) 8.92 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 11 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 106.54 Å2 Chemaxon Rotatable Bond Count 20 Chemaxon Refractivity 155.95 m3·mol-1 Chemaxon Polarizability 66.68 Å3 Chemaxon Number of Rings 5 Chemaxon Bioavailability 0 Chemaxon Rule of Five No Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule Yes Chemaxon - Predicted ADMET Features
- Not Available
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
- Chromatographic Properties
Collision Cross Sections (CCS)
Not Available
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
- 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. [Article]
- 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
- 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. [Article]
- 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
- 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. [Article]
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
- 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. [Article]
Drug created at June 28, 2018 14:58 / Updated at June 12, 2020 16:53