Opioid receptors

Oliceridine is a DEA Schedule II controlled substance. Substances in the DEA Schedule II have a high potential for abuse which may lead to severe psychological or physical dependence. It is a Opiates substance.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 μ-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 β-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 μ-opioid receptor by preferentially activating the G-protein pathway with minimal receptor phosphorylation and recruitment of β-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™.

Oliceridine is an intravenously administered, synthetic opioid that is used to treat moderate-to-severe pain not responsive to nonsteroidal antiinflammatory agents. Oliceridine is associated with a low rate of serum aminotransferase elevations during therapy but has not been linked to instances of clinically apparent liver injury. OLICERIDINE is a small molecule drug with a maximum clinical trial phase of IV that was first approved in 2020 and is indicated for pain. This drug has a black box warning from the FDA.

The Oliceridine HCl (TRV-130)  doses studied (1.5, 3, and 4.5mg) spanned the expected pharmacodynamically active range, based on pupillometry data from earlier trials. The dose of morphine (10mg) has been extensively used as a benchmark in experimental pain and was expected to produce a robust increase in hand removal latency in the CPT. Placebo was 5% dextrose in water. A single cohort of 30 individuals was selected as likely to give statistically significant effects of the morphine comparator based on past experience of the investigator.[1]
During the 11-day/10-night sequestration, subjects randomly received single doses of Oliceridine HCl (TRV-130) , placebo, or morphine intravenously ondays 1, 3, 5, 7, and 9 with assessments at baseline and at multiple timepoints postdose. Follow-up occurred approximately 7days after the last dosing period.[1]

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Tolerability[1]
Subjects were instructed to report adverse events spontaneously. In addition, at numerous set time points throughout the study, the subjects’ experience of any adverse events were captured by open-ended questions (eg, “Have you noticed any change in your health?” or “How do you feel?”). Tolerability was also measured by periodic assessments of vital signs, physical examinations, electrocardiography, oxygen saturation, and clinical laboratory values.

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Pharmacokinetics[1]
Pharmacokinetic samples were collected for plasma concentration analyses of Oliceridine HCl (TRV-130) , morphine, and morphine 6-glucuronide for 24hours after drug administration.

Absorption, Distribution and Excretion
Oliceridine administered as a single intravenous injection of 1.5, 3, or 4.5 mg in healthy male volunteers had a corresponding Cmax of 47, 76, and 119 ng/mL and a corresponding AUC0-24 of 43, 82, and 122 ng\*h/mL. Simulations of single doses of oliceridine between 1-3 mg suggest that the expected median Cmax is between 43 and 130 ng/mL while the expected median AUC is between 22 and 70 ng\*h/mL.
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.
Oliceridine has a mean steady-state volume of distribution of 90-120 L.
Healthy volunteers given doses of oliceridine between 0.15 and 7 mg had mean clearance rates between 34 and 59.6 L/h.

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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.

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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.

Hepatotoxicity
Serum ALT elevations developed in 1% to 3% of patients receiving oliceridine and in a similar proportion (2.4%) receiving morphine after abdominal surgery. However, the aminotransferase elevations were not associated with jaundice and were usually considered unrelated to therapy. Since approval of oliceridine, there have been no published reports of clinically apparent liver injury attributed to its use.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Protein Binding
Oliceridine is approximately 77% bound to plasma proteins.

[1]. Biased agonism of the μ-opioid receptor by TRV130 increases analgesia and reduces on-target adverse effects versus morphine: A randomized, double-blind, placebo-controlled, crossover study in healthy volunteers. Pain. 2014 Sep;155(9):1829-35.
[2]. https://pubchem.ncbi.nlm.nih.gov/compound/66553195

Pharmacodynamics
Oliceridine is a biased μ-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.

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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 μ, κ, δ, and opioid-like-1 (ORL1) subtypes,. However, the μ-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 Gα, β, and γ 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 Gα-GTP and a βγ heterodimer, and subsequent downstream effects. In the case of the μ-opioid receptor, the Gα-GTP directly interacts with the potassium channel Kir3 while the dissociated Gβγ 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, μ-opioid receptor activation can also result in downstream signalling through β-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 μ-opioid receptor by preferentially activating the G-protein pathway with minimal receptor phosphorylation and recruitment of β-arrestin. Competetive binding assays and structural modelling suggest that the binding site for oliceridine on the μ-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 μ-opioid receptor, specifically due to a lack of coupling with transmembrane helix six, which confers the specificity for G-protein over β-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.

HRV

386.203

1401028-24-7

1401031-39-7 (HCl)

66553195

Typically exists as solid at room temperature

5.083

1

5

7

27

471

1

COC1=C(CNCC[C@@](C2)(C3=NC=CC=C3)CCOC42CCCC4)SC=C1

DMNOVGJWPASQDL-OAQYLSRUSA-N

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

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

Oliceridine; TRV130; 1401028-24-7; TRV-130; Olinvyk; Olinvo; Oliceridine [USAN]; TRV 130;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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 (Please use freshly prepared in vivo formulations for optimal results.)