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.

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Oliceridine HCl (TRV-130)  at all doses elicited a rapid and significant increase in CPT hand removal latency from baseline compared to placebo (Fig. 2A), with peak efficacy at the first measurement 10minutes postdose (geometric means of 81, 106, and 116seconds latency for TRV130 at 1.5, 3, and 4.5mg, vs 41seconds for placebo; P<.0001). TRV130 significantly increased hand removal latency for 2 to 3hours compared to placebo at the 3- and 4.5-mg doses (P<.02), and for 1hour at the 1.5-mg dose (P<.007). TRV130 at 3 and 4.5mg also significantly (P<.02; P<.005) increased hand removal latency compared to morphine at 10 and 30minutes, after which latency was similar to morphine. There was no evidence of a sequence, period, or carry-over effect; as anticipated, there was a near absence of a response after placebo administration on the CPT. [1]

Consistent with the increased hand removal latency of Oliceridine HCl (TRV-130) , more subjects responded after TRV130, defined as a doubling of latency on at least 1 CPT, than after morphine (Fig. 2B). More subjects achieved the CPT cutoff time of 180seconds after the 3- and 4.5-mg doses of TRV130 than after morphine, suggesting that the increased efficacy of TRV130 over morphine may be underestimated at these doses because of the testing convention (Fig. 2C). In all cases, time to first perceptible pain was similar to hand removal latency (data not shown). [1]

Oliceridine HCl (TRV-130)  produced a transient reduction in respiratory drive at all doses tested (Fig. 3A), as measured by the change from baseline in minute volume in the fifth minute of hypercapnic exposure (P<.02 vs placebo for the first hour for TRV130 1.5mg and for the first 2hours at 3 and 4.5mg). The reduction in respiratory drive after morphine was similar in magnitude to the peak effect of TRV130 at 30minutes; however, unlike the transitory effect of TRV130, the effect of morphine on respiratory drive persisted through the final VRH measurement at 4hours postdose (P<.0006 vs placebo at all timepoints). The effect of morphine was significantly greater than TRV130 at 3 or 4.5mg at hours 2 through 4 (P<.01). Total reduction in minute ventilation, measured as the area under the curve over 4hours compared to placebo (Fig. 3B), was significantly less after all doses of TRV130 than after morphine (−15.9 h*L/min for morphine vs −7.3, −7.6, and −9.4 for TRV130 1.5, 3, and 4.5mg; P<.01, P<.01, and P<.05). [1]

With reduction in respiratory drive assessed by response analysis (change from baseline>average placebo response plus 1 standard deviation), more subjects experienced reduction in respiratory drive after morphine (66%) than after TRV130 (21%, 37%, and 47% at 1.5, 3, and 4.5mg) or placebo (10%). Similarly, a substantial fraction of subjects (39%) experienced a reduction in respiratory drive without a doubling CPT latency after morphine, compared to 7% to 13% after TRV130 and 10% after placebo (Fig. 3C). [1]

Oliceridine HCl (TRV-130)  elicited dose-related changes in subjective CNS effects, as measured by the DEQ. In general, TRV130 at 3mg and morphine produced similar DEQ CNS effect profiles, in the context of increased analgesia of TRV130 at 3mg (Supplementary Fig. 2), suggesting a greater therapeutic index of TRV130 relative to morphine. As measured by the DEQ (Fig. 4), more subjects experienced severe nausea after morphine (7 subjects, including 1 subject with moderate vomiting for 45minutes who was unable to complete the DEQ) than after TRV130 1.5 or 3mg (0, 1 subject); TRV130 4.5mg elicited severe total nausea with frequency similar to that of morphine. The DEQ “feeling sick” item revealed trends similar to those for the nausea item. Vomiting was not assessed in the DEQ. [1]

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.

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Disposition [1]
Of 30 subjects randomized, 29 completed the study (Supplementary Fig. 1). One subject electively discontinued for reasons unrelated to an adverse event or study procedures after completing all but the final dosing session (TRV130 1.5mg). One subject experienced sustained moderate vomiting after receiving morphine and was unable to complete pharmacodynamic assessments but remained in the study. The subject mean age (SD) was 26.9 (5.76) years. Three subjects reported ethnicity as “Hispanic or Latino”; 1 subject reported race as “black or African American.”

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Pharmacokinetics [1]
Plasma concentrations of TRV130 peaked within 10minutes of infusion and decreased in a biphasic manner, indicating rapid distribution followed by an elimination phase (Supplementary Fig. 3). Exposure to TRV130 was dose proportional with AUC0−t of 43, 82, and 122ng*h/mL for 1.5, 3, and 4.5mg TRV130. These doses were associated with peak plasma concentrations of 47, 76, and 119ng/mL.

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.

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Safety and tolerability [1]
TRV130 was generally well tolerated, with reported adverse events consistent with action at the μ-opioid receptor, including nausea, vomiting, dizziness, somnolence, pruritus/flushing, and headache (Table 1). These effects appeared to be dose-related, with TRV130 1.5mg producing a low incidence of adverse effects and TRV130 3mg producing a profile of adverse events similar to those of morphine; TRV130 4.5mg had an overall profile of adverse events similar to that of morphine but a greater incidence of nausea, dizziness, pruritus, and headache. The greater frequency of reported vomiting events after morphine (20%) than for any dose of TRV130 (0%, 3.3%, and 13.3% for TRV130 1.5, 3, and 4.5mg respectively) is consistent with the DEQ finding of more severe nausea after morphine than after any TRV130 dose, despite a similar prevalence of nausea by adverse event reporting.

[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.

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.

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Opioids provide powerful analgesia but also efficacy-limiting adverse effects, including severe nausea, vomiting, and respiratory depression, by activating μ-opioid receptors. Preclinical models suggest that differential activation of signaling pathways downstream of these receptors dissociates analgesia from adverse effects; however, this has not yet translated to a treatment with an improved therapeutic index. Thirty healthy men received single intravenous injections of the biased ligand TRV130 (1.5, 3, or 4.5mg), placebo, or morphine (10mg) in a randomized, double-blind, crossover study. Primary objectives were to measure safety and tolerability (adverse events, vital signs, electrocardiography, clinical laboratory values), and analgesia (cold pain test) versus placebo. Other measures included respiratory drive (minute volume after induced hypercapnia), subjective drug effects, and pharmacokinetics. Compared to morphine, TRV130 (3, 4.5mg) elicited higher peak analgesia (105, 116 seconds latency vs 75 seconds for morphine, P<.02), with faster onset and similar duration of action. More subjects doubled latency or achieved maximum latency (180 seconds) with TRV130 (3, 4.5mg). Respiratory drive reduction was greater after morphine than any TRV130 dose (-15.9 for morphine versus -7.3, -7.6, and -9.4 h*L/min, P<.05). More subjects experienced severe nausea after morphine (n=7) than TRV130 1.5 or 3mg (n=0, 1), but not 4.5mg (n=9). TRV130 was generally well tolerated, and exposure was dose proportional. Thus, in this study, TRV130 produced greater analgesia than morphine at doses with less reduction in respiratory drive and less severe nausea. This demonstrates early clinical translation of ligand bias as an important new concept in receptor-targeted pharmacotherapy.[1]

C22H30N2O2S

386.5508

422.179

1401031-39-7

1401028-24-7;1401031-39-7 (HCl);

68313941

Typically exists as solid at room temperature

5.083

2

5

7

28

471

1

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

YIIWXYLJZRISQP-ZMBIFBSDSA-N

InChI=1S/C22H30N2O2S.ClH/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;1H/t21-;/m1./s1

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

TRV-130; TRV 130; TRV130; Oliceridine hydrochloride; 1401031-39-7; Oliceridine HCl; TRV130 hydrochloride; TRV130 (hydrochloride); Oliceridine hydrochloride; (R)-N-((3-Methoxythiophen-2-yl)methyl)-2-(9-(pyridin-2-yl)-6-oxaspiro[4.5]decan-9-yl)ethanamine hydrochloride; XNT4TDS88V; TRV-130 Hydrochloric Acid Salt; Oliceridine; Oliceridine HCl

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Note: Please store this product in a sealed and protected environment, avoid exposure to moisture.

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.)