Loxicodegol

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

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MOLSDFPDBSMILESInChI

Similar Structures

Structure for Loxicodegol (DB14146)

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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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Contraindications & Blackbox Warnings

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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.

Target	Actions	Organism
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.

Adverse Effects

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Toxicity

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

• Alkaloids
• Heterocyclic Compounds, Fused-Ring
• Opiate Alkaloids
• Phenanthrenes

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

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. [Article]
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. [Article]
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

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

Not Available

Targets

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Details1. Mu-type opioid receptor

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. [Article]

Details2. Delta-type opioid receptor

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. [Article]

Details3. Kappa-type opioid receptor

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. [Article]

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Drug created at June 28, 2018 14:58 / Updated at June 12, 2020 16:53