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Oliceridine

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Chemistry

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Also known as: Trv130, 1401028-24-7, Trv-130, Olinvyk, Oliceridine [usan], Mcn858tcp0

Molecular Formula

C₂₂H₃₀N₂O₂S

Molecular Weight

386.6 g/mol

InChI Key

DMNOVGJWPASQDL-OAQYLSRUSA-N

FDA UNII

MCN858TCP0

Severe acute pain occurs through nociceptive signalling involving both ascending and descending spinal pathways, in which nerve conductance is mediated in part by the action of opioid receptors. Opioid receptors are seven-transmembrane G-protein-coupled receptors (GPCRs), of which the -opioid receptor subtype is predominantly targeted by and is responsible for the effects of opioid agonists. However, due to the ability of some opioid agonists to bind to other targets, as well as activation of additional downstream pathways from opioid receptors such as those involving -arrestin, the beneficial analgesic effects of opioids are coupled with severe adverse effects such as constipation and respiratory depression. Oliceridine (formerly known as TRV130) is a "biased agonist" at the -opioid receptor by preferentially activating the G-protein pathway with minimal receptor phosphorylation and recruitment of -arrestin. By acting as a biased agonist, oliceridine provides comparable analgesia compared with traditional opioids such as [morphine] at a comparable or decreased risk of opioid-related adverse effects such as constipation and respiratory depression. Oliceridine was first reported in 2013, but was initially not approved by the FDA due to concerns raised by the Anesthetic and Analgesic Drug Products Advisory Committee. Oliceridine gained FDA approval on August 7, 2020, and is currently marketed by Trevena Inc as OLINVYK.

1 2D Structure

Oliceridine

2 Identification

2.1 Computed Descriptors

2.1.1 IUPAC Name

N-[(3-methoxythiophen-2-yl)methyl]-2-[(9R)-9-pyridin-2-yl-6-oxaspiro[4.5]decan-9-yl]ethanamine

2.1.2 InChI

InChI=1S/C22H30N2O2S/c1-25-18-7-15-27-19(18)16-23-13-10-21(20-6-2-5-12-24-20)11-14-26-22(17-21)8-3-4-9-22/h2,5-7,12,15,23H,3-4,8-11,13-14,16-17H2,1H3/t21-/m1/s1

2.1.3 InChI Key

DMNOVGJWPASQDL-OAQYLSRUSA-N

2.1.4 Canonical SMILES

COC1=C(SC=C1)CNCCC2(CCOC3(C2)CCCC3)C4=CC=CC=N4

2.1.5 Isomeric SMILES

COC1=C(SC=C1)CNCC[C@]2(CCOC3(C2)CCCC3)C4=CC=CC=N4

2.2 Other Identifiers

2.2.1 UNII

MCN858TCP0

2.3 Synonyms

2.3.1 MeSH Synonyms

1. ((3-methoxythiophen-2-yl)methyl)((2-(9-(pyridin-2-yl)-6-oxaspiro(4.5)decan-9-yl)ethyl))amine

2. Olinvyk

3. Trv-130

4. Trv130

2.3.2 Depositor-Supplied Synonyms

1. Trv130

2. 1401028-24-7

3. Trv-130

4. Olinvyk

5. Oliceridine [usan]

6. Mcn858tcp0

7. N-[(3-methoxythiophen-2-yl)methyl]-2-[(9r)-9-pyridin-2-yl-6-oxaspiro[4.5]decan-9-yl]ethanamine

8. Olinvo

9. [(3-methoxythiophen-2-yl)methyl]({2-[(9r)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine

10. 6-oxaspiro(4.5)decane-9-ethanamine, N-((3-methoxy-2-thienyl)methyl)-9-(2-pyridinyl)-, (9r)-

11. 6-oxaspiro[4.5]decane-9-ethanamine, N-[(3-methoxy-2-thienyl)methyl]-9-(2-pyridinyl)-, (9r)-

12. N-((3-methoxythiophen-2-yl)methyl)-2-((9r)-9-(pyridin-2-yl)-6-oxaspiro(4.5)decan-9-yl)ethanamine

13. N-[(3-methoxythiophen-2-yl)methyl]-2-[(9r)-9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethan-1-amine

14. Trv 130

15. Unii-mcn858tcp0

16. Trv130a

17. Olinvyk (tn)

18. Oliceridine [mi]

19. Oliceridine; Trv-130

20. Oliceridine [inn]

21. Oliceridine (usan/inn)

22. Oliceridine [who-dd]

23. Gtpl7334

24. Chembl2443262

25. Schembl12542370

26. Oliceridine [orange Book]

27. Dtxsid201031292

28. Bcp14196

29. Bgc02824

30. Ex-a2170

31. Bdbm50493818

32. Zinc96940334

33. Akos030526482

34. Oliceridine;olinvo;trv 130;trv130

35. Cs-3571

36. Db14881

37. Ncgc00390659-01

38. Ac-35966

39. Hy-16655

40. A14337

41. D11214

42. A935006

43. Q17142898

44. (9r)-n-[(3-methoxy-2-thienyl)methyl]-9-(2-pyridinyl)-6-oxaspiro[4.5]decane-9-ethanamine Hydrochlorid

45. (r)-n-((3-methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine

46. [(3-methoxythiophen-2-yl)methyl]({2-[(9r)-9-(pyridine-2-yl)-6-oxaspiro[4.5]decan-9-yl]ethyl})amine

47. Wh2

2.4 Create Date

2012-11-05

3 Chemical and Physical Properties

Molecular Formula	C₂₂H₃₀N₂O₂S
Molecular Weight	386.6 g/mol
XLogP3	3.5
Hydrogen Bond Donor Count	1
Hydrogen Bond Acceptor Count	5
Rotatable Bond Count	7
Exact Mass	386.20279938 g/mol
Monoisotopic Mass	386.20279938 g/mol
Topological Polar Surface Area	71.6 Å²
Heavy Atom Count	27
Formal Charge	0
Complexity	471
Isotope Atom Count	0
Defined Atom Stereocenter Count	1
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

Oliceridine is indicated for the management of acute pain in adults severe enough to require intravenous opioid analgesics and for whom no acceptable alternative treatments exist.

5 Pharmacology and Biochemistry

5.1 Pharmacology

Oliceridine is a biased -opioid receptor agonist that acts through downstream signalling pathways to exert antinociceptive analgesia in patients experience severe acute pain. Results from multiple clinical studies and simulation data demonstrate that oliceridine exerts significant analgesic benefits within 5-20 minutes following administration but dissipates quickly with a half-life between one and three hours. Despite an improved adverse effect profile over conventional opioids, oliceridine carries important clinical warnings. Oliceridine has the potential to cause severe respiratory depression, especially in patients who are elderly, cachectic, debilitated, or who otherwise have chronically impaired pulmonary function. In addition, severe respiratory depression or sedation may occur in patients with increased intracranial pressure, head injury, brain tumour, or impaired consciousness. Patients with adrenal insufficiency or severe hypotension may require treatment alterations or discontinuation. Finally, oliceridine has been demonstrated to prolong the QTc interval and has not been properly evaluated beyond a maximum daily dose of 27 mg; it is recommended not to exceed 27 mg per day.

5.2 ATC Code

N - Nervous system

N02 - Analgesics

N02A - Opioids

N02AX - Other opioids

N02AX07 - Oliceridine

5.3 Absorption, Distribution and Excretion

Absorption

Oliceridine administered as a single intravenous injection of 1.5, 3, or 4.5 mg in healthy male volunteers had a corresponding C_max of 47, 76, and 119 ng/mL and a corresponding AUC_0-24 of 43, 82, and 122 ng\*h/mL. Simulations of single doses of oliceridine between 1-3 mg suggest that the expected median C_max is between 43 and 130 ng/mL while the expected median AUC is between 22 and 70 ng\*h/mL.

Route of Elimination

Approximately 70% of oliceridine is eliminated via the renal route, of which only 0.97-6.75% of an initial dose is recovered unchanged. The remaining 30% is eliminated in feces.

Volume of Distribution

Oliceridine has a mean steady-state volume of distribution of 90-120 L.

Clearance

Healthy volunteers given doses of oliceridine between 0.15 and 7 mg had mean clearance rates between 34 and 59.6 L/h.

5.4 Metabolism/Metabolites

Oliceridine is primarily metabolized hepatically by CYP3A4 and CYP2D6 _in vitro_, with minor contributions from CYP2C9 and CYP2C19. None of oliceridine's metabolites are known to be active. Metabolic pathways include N-dealkylation, glucuronidation, and dehydrogenation.

5.5 Biological Half-Life

Oliceridine has a half-life of 1.3-3 hours while its metabolites, none of which are known to be active, have a substantially longer half-life of 44 hours.

5.6 Mechanism of Action

Pain perception follows a complex pathway initiated in primary sensory neurons, subsequently transmitted to the spinal cord dorsal horn and through ascending axons to multiple regions within the thalamus, brainstem, and midbrain, and finally relayed through descending signals that either inhibit or facilitate the nociceptive signalling. Opioid receptors are seven-transmembrane G-protein-coupled receptors (GPCRs) that can be divided into , , , and opioid-like-1 (ORL1) subtypes,. However, the -opioid receptor is predominantly targeted by and is responsible for the effects of traditional opioids. GPCRs in the inactive state are bound intracellularly by a complex consisting of a G, , and subunit together with guanosine diphosphate (GDP). Activation of the GPCR through extracellular agonist binding catalyzes the replacement of GDP with guanosine triphosphate (GTP), dissociation of both G-GTP and a heterodimer, and subsequent downstream effects. In the case of the -opioid receptor, the G-GTP directly interacts with the potassium channel K_ir3 while the dissociated G subunit directly binds to and occludes the pore of P/Q-, N-, and L-type Ca²⁺ channels. Furthermore, opioid receptor activation inhibits adenylyl cyclase, which in turn reduces cAMP-dependent Ca²⁺ influx. By altering membrane ion conductivity, these effects modulate nociceptive signalling and produce an analgesic effect. In addition to the G-protein pathway, -opioid receptor activation can also result in downstream signalling through -arrestin, which results in receptor internalization and is associated with negative effects of opioid use including respiratory depression, gastrointestinal effects, and desensitization/tolerance. Oliceridine acts as a "biased agonist" at the -opioid receptor by preferentially activating the G-protein pathway with minimal receptor phosphorylation and recruitment of -arrestin. Competetive binding assays and structural modelling suggest that the binding site for oliceridine on the -opioid receptor is the same as for classical opioids. However, molecular modelling supports a model whereby oliceridine binding induces a different intracellular conformation of the -opioid receptor, specifically due to a lack of coupling with transmembrane helix six, which confers the specificity for G-protein over -arrestin interaction. Numerous _in vitro_, _in vivo_, and clinical studies support the view that this biased agonism results in comparable analgesia compared with traditional opioids at a comparable or decreased risk of opioid-related adverse effects such as constipation and respiratory depression.