Oliceridine

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Identification

Summary

Oliceridine is a biased opioid agonist indicated for the management of severe acute pain in adult patients. Through preferential activation of G-protein-coupled signalling pathways, oliceridine provides analgesic effect with a comparable or improved safety profile over conventional opioid agonists.

Brand Names

Olinvyk

Generic Name

Oliceridine

DrugBank Accession Number

DB14881

Background

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.^4,5 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.^2,5 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.^1,2,3,4,5

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.^1,2 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.^{1,2,6,7,8,9,10,15}

Oliceridine was first reported in 2013,^1,14 but was initially not approved by the FDA due to concerns raised by the Anesthetic and Analgesic Drug Products Advisory Committee.⁴ Oliceridine gained FDA approval on August 7, 2020, and is currently marketed by Trevena Inc as OLINVYK™.¹⁵

Type

Small Molecule

Groups

Approved, Investigational

Structure

3D

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MOLSDF3D-SDFPDBSMILESInChI

Similar Structures

Structure for Oliceridine (DB14881)

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Weight

Average: 386.55
Monoisotopic: 386.202799388

Chemical Formula

C₂₂H₃₀N₂O₂S

Synonyms

• Oliceridine

External IDs

• TRV 130
• TRV-130
• TRV130

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Pharmacology

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.¹⁵

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Associated Conditions

Indication Type	Indication	Combined Product Details	Approval Level	Age Group	Patient Characteristics	Dose Form
Management of	Severe pain, acute		••••••••••••	•••••	•••••••••• ••••••••••• ••••••••• •••••••	••••••••

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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.^1,2,3,4,5,15 Results from multiple clinical studies^{6,7,8,9,10,15} and simulation data^11,12 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.^{6,7,8,9,10,15} Despite an improved adverse effect profile over conventional opioids^{6,7,8,9,10,15}, 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.¹⁵

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.^4,5 Opioid receptors are seven-transmembrane G-protein-coupled receptors (GPCRs) that can be divided into μ, κ, δ, and opioid-like-1 (ORL1) subtypes,^2,5. However, the μ-opioid receptor is predominantly targeted by and is responsible for the effects of traditional opioids.⁵ GPCRs in the inactive state are bound intracellularly by a complex consisting of a G_α, 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 G_α-GTP and a βγ heterodimer, and subsequent downstream effects.⁵

In the case of the μ-opioid receptor, the G_α-GTP directly interacts with the potassium channel K_ir3 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.^3,4,5 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.^1,2,3,4,5

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.^1,2 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.^1,13 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.¹³ 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.^{1,2,6,7,8,9,10,15}

Target	Actions	Organism
AMu-type opioid receptor	agonist	Humans

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.⁶ 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.¹²

Volume of distribution

Oliceridine has a mean steady-state volume of distribution of 90-120 L.¹⁵

Protein binding

Oliceridine is approximately 77% bound to plasma proteins.¹⁵

Metabolism

Oliceridine is primarily metabolized hepatically by CYP3A4 and CYP2D6 in vitro, with minor contributions from CYP2C9 and CYP2C19.¹⁵ None of oliceridine's metabolites are known to be active.^5,15 Metabolic pathways include N-dealkylation, glucuronidation, and dehydrogenation.¹⁵

Hover over products below to view reaction partners

• Oliceridine
  • Oxy-oliceridine
    • TRV0306954
  • TRV0109662

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.¹⁵

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.¹⁵

Clearance

Healthy volunteers given doses of oliceridine between 0.15 and 7 mg had mean clearance rates between 34 and 59.6 L/h.^11,12

Adverse Effects

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Toxicity

Symptoms of oliceridine overdose are variable but can include respiratory depression, airway obstruction, pulmonary edema, bradycardia, hypotension, muscle flaccidity, cold skin, and somnolence progressing to either stupor or coma. Miosis is commonly observed but in cases of severe hypoxia, mydriasis may be observed instead. Oliceridine overdose may be fatal. In case of overdose, the establishment of a protected airway followed by the institution of assisted or controlled ventilation is a high priority; in case of cardiac arrhythmias or arrest, additional supportive measures may be immediately required. Supportive treatment, including oxygen, vasopressors, and the administration of an opioid antagonist such as naloxone may be applied but should be tailored to the individual patient's condition.¹⁵

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.

• Approved
• Vet approved
• Nutraceutical
• Illicit
• Withdrawn
• Investigational
• Experimental
• All Drugs

Drug	Interaction
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1,2-Benzodiazepine	The risk or severity of hypotension, sedation, death, somnolence, and respiratory depression can be increased when 1,2-Benzodiazepine is combined with Oliceridine.
Abametapir	The serum concentration of Oliceridine can be increased when it is combined with Abametapir.
Abatacept	The metabolism of Oliceridine can be increased when combined with Abatacept.
Abiraterone	The serum concentration of Oliceridine can be increased when it is combined with Abiraterone.
Acebutolol	The metabolism of Oliceridine can be decreased when combined with Acebutolol.

Food Interactions

No interactions found.

Products

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International/Other Brands

Olinvo / Olinvyk

Brand Name Prescription Products

Name	Dosage	Strength	Route	Labeller	Marketing Start	Marketing End	Region	Image
Olinvyk	Injection, solution	2 mg/2mL	Intravenous	Trevena, Inc.	2020-08-07	Not applicable
Olinvyk	Injection, solution	1 mg/1mL	Intravenous	Trevena, Inc.	2020-08-07	Not applicable
Olinvyk	Injection, solution	30 mg/30mL	Intravenous	Trevena, Inc.	2020-08-07	Not applicable

Categories

ATC Codes

N02AX07 — Oliceridine

• N02AX — Other opioids
• N02A — OPIOIDS
• N02 — ANALGESICS
• N — NERVOUS SYSTEM

Drug Categories

• Analgesics
• Anesthetics
• Central Nervous System Agents
• Central Nervous System Depressants
• Cytochrome P-450 CYP2C19 Substrates
• Cytochrome P-450 CYP2C9 Substrates
• Cytochrome P-450 CYP2D6 Substrates
• Cytochrome P-450 CYP3A Substrates
• Cytochrome P-450 CYP3A4 Substrates
• Cytochrome P-450 Substrates
• Ligands
• Narcotics
• Nervous System
• Neuraxial Anesthetics
• Opiate Agonists
• Opioid Agonist
• Opioids
• Peripheral Nervous System Agents
• Sensory System Agents
• Serotonergic Drugs Shown to Increase Risk of Serotonin Syndrome
• Sulfur Compounds

Classification

Not classified

Affected organisms

• Humans and other mammals

Chemical Identifiers

UNII

MCN858TCP0

CAS number

1401028-24-7

InChI Key

DMNOVGJWPASQDL-OAQYLSRUSA-N

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

IUPAC Name

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

SMILES

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

References

Synthesis Reference

Chen XT, Pitis P, Liu G, Yuan C, Gotchev D, Cowan CL, Rominger DH, Koblish M, Dewire SM, Crombie AL, Violin JD, Yamashita DS: Structure-activity relationships and discovery of a G protein biased mu opioid receptor ligand, (3-methoxythiophen-2-yl)methylamine (TRV130), for the treatment of acute severe pain. J Med Chem. 2013 Oct 24;56(20):8019-31. doi: 10.1021/jm4010829.

General References

1. DeWire SM, Yamashita DS, Rominger DH, Liu G, Cowan CL, Graczyk TM, Chen XT, Pitis PM, Gotchev D, Yuan C, Koblish M, Lark MW, Violin JD: A G protein-biased ligand at the mu-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J Pharmacol Exp Ther. 2013 Mar;344(3):708-17. doi: 10.1124/jpet.112.201616. Epub 2013 Jan 8. [Article]
2. Manglik A, Lin H, Aryal DK, McCorvy JD, Dengler D, Corder G, Levit A, Kling RC, Bernat V, Hubner H, Huang XP, Sassano MF, Giguere PM, Lober S, Da Duan, Scherrer G, Kobilka BK, Gmeiner P, Roth BL, Shoichet BK: Structure-based discovery of opioid analgesics with reduced side effects. Nature. 2016 Sep 8;537(7619):185-190. doi: 10.1038/nature19112. Epub 2016 Aug 17. [Article]
3. Ok HG, Kim SY, Lee SJ, Kim TK, Huh BK, Kim KH: Can oliceridine (TRV130), an ideal novel micro receptor G protein pathway selective (micro-GPS) modulator, provide analgesia without opioid-related adverse reactions? Korean J Pain. 2018 Apr;31(2):73-79. doi: 10.3344/kjp.2018.31.2.73. Epub 2018 Apr 2. [Article]
4. Azzam AAH, McDonald J, Lambert DG: Hot topics in opioid pharmacology: mixed and biased opioids. Br J Anaesth. 2019 Jun;122(6):e136-e145. doi: 10.1016/j.bja.2019.03.006. Epub 2019 Apr 19. [Article]
5. Urits I, Viswanath O, Orhurhu V, Gress K, Charipova K, Kaye AD, Ngo A: The Utilization of Mu-Opioid Receptor Biased Agonists: Oliceridine, an Opioid Analgesic with Reduced Adverse Effects. Curr Pain Headache Rep. 2019 Mar 18;23(5):31. doi: 10.1007/s11916-019-0773-1. [Article]
6. Soergel DG, Subach RA, Burnham N, Lark MW, James IE, Sadler BM, Skobieranda F, Violin JD, Webster LR: Biased agonism of the mu-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. doi: 10.1016/j.pain.2014.06.011. Epub 2014 Jun 19. [Article]
7. Viscusi ER, Webster L, Kuss M, Daniels S, Bolognese JA, Zuckerman S, Soergel DG, Subach RA, Cook E, Skobieranda F: A randomized, phase 2 study investigating TRV130, a biased ligand of the mu-opioid receptor, for the intravenous treatment of acute pain. Pain. 2016 Jan;157(1):264-72. doi: 10.1097/j.pain.0000000000000363. [Article]
8. Singla N, Minkowitz HS, Soergel DG, Burt DA, Subach RA, Salamea MY, Fossler MJ, Skobieranda F: A randomized, Phase IIb study investigating oliceridine (TRV130), a novel micro-receptor G-protein pathway selective (mu-GPS) modulator, for the management of moderate to severe acute pain following abdominoplasty. J Pain Res. 2017 Oct 6;10:2413-2424. doi: 10.2147/JPR.S137952. eCollection 2017. [Article]
9. Singla NK, Skobieranda F, Soergel DG, Salamea M, Burt DA, Demitrack MA, Viscusi ER: APOLLO-2: A Randomized, Placebo and Active-Controlled Phase III Study Investigating Oliceridine (TRV130), a G Protein-Biased Ligand at the mu-Opioid Receptor, for Management of Moderate to Severe Acute Pain Following Abdominoplasty. Pain Pract. 2019 Sep;19(7):715-731. doi: 10.1111/papr.12801. Epub 2019 Jun 24. [Article]
10. Viscusi ER, Skobieranda F, Soergel DG, Cook E, Burt DA, Singla N: APOLLO-1: a randomized placebo and active-controlled phase III study investigating oliceridine (TRV130), a G protein-biased ligand at the micro-opioid receptor, for management of moderate-to-severe acute pain following bunionectomy. J Pain Res. 2019 Mar 11;12:927-943. doi: 10.2147/JPR.S171013. eCollection 2019. [Article]
11. Fossler MJ, Sadler BM, Farrell C, Burt DA, Pitsiu M, Skobieranda F, Soergel DG: Oliceridine, a Novel G Protein-Biased Ligand at the mu-Opioid Receptor, Demonstrates a Predictable Relationship Between Plasma Concentrations and Pain Relief. II: Simulation of Potential Phase 3 Study Designs Using a Pharmacokinetic/Pharmacodynamic Model. J Clin Pharmacol. 2018 Jun;58(6):762-770. doi: 10.1002/jcph.1075. Epub 2018 Feb 2. [Article]
12. Fossler MJ, Sadler BM, Farrell C, Burt DA, Pitsiu M, Skobieranda F, Soergel DG: Oliceridine (TRV130), a Novel G Protein-Biased Ligand at the mu-Opioid Receptor, Demonstrates a Predictable Relationship Between Plasma Concentrations and Pain Relief. I: Development of a Pharmacokinetic/Pharmacodynamic Model. J Clin Pharmacol. 2018 Jun;58(6):750-761. doi: 10.1002/jcph.1076. Epub 2018 Feb 7. [Article]
13. Schneider S, Provasi D, Filizola M: How Oliceridine (TRV-130) Binds and Stabilizes a mu-Opioid Receptor Conformational State That Selectively Triggers G Protein Signaling Pathways. Biochemistry. 2016 Nov 22;55(46):6456-6466. doi: 10.1021/acs.biochem.6b00948. Epub 2016 Nov 7. [Article]
14. Chen XT, Pitis P, Liu G, Yuan C, Gotchev D, Cowan CL, Rominger DH, Koblish M, Dewire SM, Crombie AL, Violin JD, Yamashita DS: Structure-activity relationships and discovery of a G protein biased mu opioid receptor ligand, [(3-methoxythiophen-2-yl)methyl]({2-[(9R)-9-(pyridin-2-yl)-6-oxaspiro-[4.5]decan- 9-yl]ethyl})amine (TRV130), for the treatment of acute severe pain. J Med Chem. 2013 Oct 24;56(20):8019-31. doi: 10.1021/jm4010829. Epub 2013 Oct 14. [Article]
15. FDA Approved Drug Products: Olinvyk (oliceridine) injection [Link]
16. FDA Briefing Document: Oliceridine [Link]
17. FDA Approved Drug Products: OLINVYK (oliceridine) injection, for intravenous use, CII (Jan 2024) [Link]

External Links

ChemSpider

30841043

BindingDB

50493818

RxNav

2392230

ChEMBL

CHEMBL2443262

ZINC

ZINC000096940334

PDBe Ligand

WH2

Wikipedia

Oliceridine

PDB Entries

8efb

Clinical Trials

Clinical Trials

Clinical Trial & Rare Diseases Add-on Data Package

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Phase	Status	Purpose	Conditions	Count	Start Date	Why Stopped	100+ additional columns
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4	Completed	Treatment	Acute Pain / Adverse Drug Reaction (ADR) / Burns / Post Operative Nausea and Vomiting (PONV) / Respiratory Depression	1	somestatus	stop reason	just information to hide
4	Not Yet Recruiting	Prevention	Post Operative Nausea and Vomiting (PONV)	1	somestatus	stop reason	just information to hide
4	Not Yet Recruiting	Treatment	Acute Pain / Opioid Analgesic Adverse Reaction	1	somestatus	stop reason	just information to hide
4	Not Yet Recruiting	Treatment	Analgesia	1	somestatus	stop reason	just information to hide
4	Recruiting	Prevention	Major Surgery	1	somestatus	stop reason	just information to hide

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Pharmacoeconomics

Manufacturers

Not Available

Packagers

Not Available

Dosage Forms

Form	Route	Strength
Injection, solution	Intravenous	1 mg/1mL
Injection, solution	Intravenous	2 mg/2mL
Injection, solution	Intravenous	30 mg/30mL

Prices

Not Available

Patents

Patent Number	Pediatric Extension	Approved	Expires (estimated)	Region
US9642842	No	2017-05-09	2032-03-23
US8835488	No	2014-09-16	2032-03-23
US9309234	No	2016-04-12	2032-03-23
US11077098	No	2021-08-03	2032-03-23
US11931350	No	2012-03-23	2032-03-23

Properties

State

Solid

Experimental Properties

Property	Value	Source
logP	3.19	DeWire SM, Yamashita DS, Rominger DH, Liu G, Cowan CL, Graczyk TM, Chen XT, Pitis PM, Gotchev D, Yuan C, Koblish M, Lark MW, Violin JD: A G protein-biased ligand at the mu-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J Pharmacol Exp Ther. 2013 Mar;344(3):708-17. doi: 10.1124/jpet.112.201616.

Predicted Properties

Property	Value	Source
Water Solubility	0.00131 mg/mL	ALOGPS
logP	3.88	ALOGPS
logP	3.96	Chemaxon
logS	-5.5	ALOGPS
pKa (Strongest Basic)	9.12	Chemaxon
Physiological Charge	1	Chemaxon
Hydrogen Acceptor Count	4	Chemaxon
Hydrogen Donor Count	1	Chemaxon
Polar Surface Area	43.38 Å2	Chemaxon
Rotatable Bond Count	7	Chemaxon
Refractivity	108.97 m3·mol-1	Chemaxon
Polarizability	43.59 Å3	Chemaxon
Number of Rings	4	Chemaxon
Bioavailability	1	Chemaxon
Rule of Five	Yes	Chemaxon
Ghose Filter	Yes	Chemaxon
Veber's Rule	No	Chemaxon
MDDR-like Rule	Yes	Chemaxon

Predicted ADMET Features

Not Available

Spectra

Mass Spec (NIST)

Not Available

Spectra

Spectrum	Spectrum Type	Splash Key
Predicted MS/MS Spectrum - 10V, Positive (Annotated)	Predicted LC-MS/MS	splash10-000i-0009000000-7f800b977e3bd2463b16
Predicted MS/MS Spectrum - 10V, Negative (Annotated)	Predicted LC-MS/MS	splash10-000i-0009000000-20d2781da9196f208eea
Predicted MS/MS Spectrum - 20V, Positive (Annotated)	Predicted LC-MS/MS	splash10-000i-0139000000-4d44624a9e5ec1a689a9
Predicted MS/MS Spectrum - 20V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0zfr-1149000000-d36ec647ab0a9c2fe89c
Predicted MS/MS Spectrum - 40V, Negative (Annotated)	Predicted LC-MS/MS	splash10-0fvi-3329000000-c418cf8c00a3aebbe163
Predicted MS/MS Spectrum - 40V, Positive (Annotated)	Predicted LC-MS/MS	splash10-00m1-5695000000-345e4dba2b8da4fa60db
Predicted 1H NMR Spectrum	1D NMR	Not Applicable
Predicted 13C NMR Spectrum	1D NMR	Not Applicable

Chromatographic Properties

Collision Cross Sections (CCS)

Not Available

Targets

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Details1. Mu-type opioid receptor

Kind

Protein

Organism

Humans

Pharmacological action

Yes

Actions

Agonist

Curator comments

Oliceridine is approximately 400-fold selective for the mu-type opioid receptor over all other opioid receptor subtypes in cell-based assays.

General Function

Receptor for endogenous opioids such as beta-endorphin and endomorphin (PubMed:10529478, PubMed:12589820, PubMed:7891175, PubMed:7905839, PubMed:7957926, PubMed:9689128). Receptor for natural and synthetic opioids including morphine, heroin, DAMGO, fentanyl, etorphine, buprenorphin and methadone (PubMed:10529478, PubMed:10836142, PubMed:12589820, PubMed:19300905, PubMed:7891175, PubMed:7905839, PubMed:7957926, PubMed:9689128). Also activated by enkephalin peptides, such as Met-enkephalin or Met-enkephalin-Arg-Phe, with higher affinity for Met-enkephalin-Arg-Phe (By similarity). Agonist binding to the receptor induces coupling to an inactive GDP-bound heterotrimeric G-protein complex and subsequent exchange of GDP for GTP in the G-protein alpha subunit leading to dissociation of the G-protein complex with the free GTP-bound G-protein alpha and the G-protein beta-gamma dimer activating downstream cellular effectors (PubMed:7905839). The agonist- and cell type-specific activity is predominantly coupled to pertussis toxin-sensitive G(i) and G(o) G alpha proteins, GNAI1, GNAI2, GNAI3 and GNAO1 isoforms Alpha-1 and Alpha-2, and to a lesser extent to pertussis toxin-insensitive G alpha proteins GNAZ and GNA15 (PubMed:12068084). They mediate an array of downstream cellular responses, including inhibition of adenylate cyclase activity and both N-type and L-type calcium channels, activation of inward rectifying potassium channels, mitogen-activated protein kinase (MAPK), phospholipase C (PLC), phosphoinositide/protein kinase (PKC), phosphoinositide 3-kinase (PI3K) and regulation of NF-kappa-B (By similarity). Also couples to adenylate cyclase stimulatory G alpha proteins (By similarity). The selective temporal coupling to G-proteins and subsequent signaling can be regulated by RGSZ proteins, such as RGS9, RGS17 and RGS4 (By similarity). Phosphorylation by members of the GPRK subfamily of Ser/Thr protein kinases and association with beta-arrestins is involved in short-term receptor desensitization (By similarity). Beta-arrestins associate with the GPRK-phosphorylated receptor and uncouple it from the G-protein thus terminating signal transduction (By similarity). The phosphorylated receptor is internalized through endocytosis via clathrin-coated pits which involves beta-arrestins (By similarity). The activation of the ERK pathway occurs either in a G-protein-dependent or a beta-arrestin-dependent manner and is regulated by agonist-specific receptor phosphorylation (By similarity). Acts as a class A G-protein coupled receptor (GPCR) which dissociates from beta-arrestin at or near the plasma membrane and undergoes rapid recycling (By similarity). Receptor down-regulation pathways are varying with the agonist and occur dependent or independent of G-protein coupling (By similarity). Endogenous ligands induce rapid desensitization, endocytosis and recycling (By similarity). Heterooligomerization with other GPCRs can modulate agonist binding, signaling and trafficking properties (By similarity)

Specific Function

beta-endorphin receptor activity

Gene Name

OPRM1

Uniprot ID

P35372

Uniprot Name

Mu-type opioid receptor

Molecular Weight

44778.855 Da

References

1. Schneider S, Provasi D, Filizola M: How Oliceridine (TRV-130) Binds and Stabilizes a mu-Opioid Receptor Conformational State That Selectively Triggers G Protein Signaling Pathways. Biochemistry. 2016 Nov 22;55(46):6456-6466. doi: 10.1021/acs.biochem.6b00948. Epub 2016 Nov 7. [Article]
2. DeWire SM, Yamashita DS, Rominger DH, Liu G, Cowan CL, Graczyk TM, Chen XT, Pitis PM, Gotchev D, Yuan C, Koblish M, Lark MW, Violin JD: A G protein-biased ligand at the mu-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J Pharmacol Exp Ther. 2013 Mar;344(3):708-17. doi: 10.1124/jpet.112.201616. Epub 2013 Jan 8. [Article]
3. Manglik A, Lin H, Aryal DK, McCorvy JD, Dengler D, Corder G, Levit A, Kling RC, Bernat V, Hubner H, Huang XP, Sassano MF, Giguere PM, Lober S, Da Duan, Scherrer G, Kobilka BK, Gmeiner P, Roth BL, Shoichet BK: Structure-based discovery of opioid analgesics with reduced side effects. Nature. 2016 Sep 8;537(7619):185-190. doi: 10.1038/nature19112. Epub 2016 Aug 17. [Article]
4. Urits I, Viswanath O, Orhurhu V, Gress K, Charipova K, Kaye AD, Ngo A: The Utilization of Mu-Opioid Receptor Biased Agonists: Oliceridine, an Opioid Analgesic with Reduced Adverse Effects. Curr Pain Headache Rep. 2019 Mar 18;23(5):31. doi: 10.1007/s11916-019-0773-1. [Article]
5. FDA Approved Drug Products: Olinvyk (oliceridine) injection [Link]

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Drug created at May 20, 2019 14:32 / Updated at January 19, 2024 13:35