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Loxicodegol

Loxicodegol

Synopsis, Chemistry

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Also known as: Oxycodegol, Oxycodegol [usan], Nktr-181, J2wiv0jmml, Oxycodegol (usan), 1211231-76-3

Molecular Formula

C₃₁H₄₉NO₁₀

Molecular Weight

595.7 g/mol

InChI Key

RQHILGKAOIGUHU-XPLSERNMSA-N

FDA UNII

J2WIV0JMML

Loxicodegol was developed by Nektar Therapeutics as an opioid analgesic with low abuse potential for the treatment of chronic pain. 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. 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

1 2D Structure

Loxicodegol

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

(4R,4aS,7S,7aR,12bS)-9-methoxy-7-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-3-methyl-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-4a-ol

2.1.2 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

2.1.3 InChI Key

RQHILGKAOIGUHU-XPLSERNMSA-N

2.1.4 Canonical SMILES

CN1CCC23C4C(CCC2(C1CC5=C3C(=C(C=C5)OC)O4)O)OCCOCCOCCOCCOCCOCCOC

2.1.5 Isomeric SMILES

CN1CC[C@]23[C@@H]4[C@H](CC[C@]2([C@H]1CC5=C3C(=C(C=C5)OC)O4)O)OCCOCCOCCOCCOCCOCCOC

2.2 Other Identifiers

2.2.1 UNII

J2WIV0JMML

2.3 Synonyms

2.3.1 MeSH Synonyms

1. 4,5-epoxy-6-(3,6,9,12,15,18-hexaoxanonadec-1-yloxy)-3-methoxy-17-methylmorphinan-14-ol

2. Nktr-181

2.3.2 Depositor-Supplied Synonyms

1. Oxycodegol

2. Oxycodegol [usan]

3. Nktr-181

4. J2wiv0jmml

5. Oxycodegol (usan)

6. 1211231-76-3

7. Oxicodegol

8. Loxicodegol [inn]

9. Unii-j2wiv0jmml

10. Oxycodegol [inn]

11. Loxicodegol (deleted Inn)

12. Loxicodegol [who-dd]

13. Nktr181

14. Gtpl10652

15. Who 9971

16. Db14146

17. Cs-0033429

18. D11424

19. (4r,4as,7s,7ar,12bs)-9-methoxy-7-[2-[2-[2-[2-[2-(2-methoxyethoxy)ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]-3-methyl-1,2,4,5,6,7,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinolin-4a-ol

20. 4,5.alpha.-epoxy-6.alpha.-((2,5,8,11,14,17-hexaoxanonadecan-19-yl)oxy)-3-methoxy-17-methylmorphinan-14-ol

21. 4,5alpha-epoxy-6alpha-((2,5,8,11,14,17-hexaoxanonadecan-19-yl)oxy)-3-methoxy-17-methylmorphinan-14-ol

22. Morphinan-14-ol, 4,5-epoxy-6-(3,6,9,12,15,18-hexaoxanonadec-1-yloxy)-3-methoxy-17-methyl-, (5.alpha.,6.alpha.)-

2.4 Create Date

2014-05-19

3 Chemical and Physical Properties

Molecular Formula	C₃₁H₄₉NO₁₀
Molecular Weight	595.7 g/mol
XLogP3	-1.1
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	11
Rotatable Bond Count	20
Exact Mass	595.33564676 g/mol
Monoisotopic Mass	595.33564676 g/mol
Topological Polar Surface Area	107 Å²
Heavy Atom Count	42
Formal Charge	0
Complexity	808
Isotope Atom Count	0
Defined Atom Stereocenter Count	5
Undefined Atom Stereocenter Count	0
Defined Bond Stereocenter Count	0
Undefined Bond Stereocenter Count	0
Covalently Bonded Unit Count	1

4 Drug and Medication Information

4.1 Drug Indication

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

5 Pharmacology and Biochemistry

5.1 Pharmacology

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. The safety profile of Loxicodegol is much improved from that of other opioid analgesics. 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

5.2 Absorption, Distribution and Excretion

Absorption

Loxicodegol has a Tmax of 1.8h and a bioavailability of 34% with oral administration. It enters the brain about 17-70 times more slowly than oxycodone. 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.

Clearance

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

5.3 Biological Half-Life

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

5.4 Mechanism of Action

Loxicodegol is a full agonist at the -opioid receptor. It also displays selectivity towards this subtype with an affinity of 237 nM compared to 4150 nM and >100000 nM for the - and -opioid receptors. The -opioid receptor is activated with an EC of 12.5 M. Activation of this receptor produces an inhibitory effect on neurotransmission through Gi/Go coupling. Opioid medications like Loxicodegol inhibit voltage gated Ca 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.