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κ receptor

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Target not currently curated in GtoImmuPdb

Target id: 318

Nomenclature: κ receptor

Family: Opioid receptors

Contents:

Gene and Protein Information Click here for help
class A G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 380 8q11.23 OPRK1 opioid receptor kappa 1 65,103,135
Mouse 7 380 1 1.89 cM Oprk1 opioid receptor, kappa 1 8,47,61,77,128
Rat 7 380 5q12 Oprk1 opioid receptor, kappa 1 16,59,67-68,76
Previous and Unofficial Names Click here for help
KOR-1 | Kappa receptor | OP2 | KOP | KOPr
Database Links Click here for help
Specialist databases
GPCRdb oprk_human (Hs), oprk_mouse (Mm), oprk_rat (Rn)
Other databases
Alphafold P41145 (Hs), P33534 (Mm), P34975 (Rn)
ChEMBL Target CHEMBL237 (Hs), CHEMBL4329 (Mm), CHEMBL3614 (Rn)
DrugBank Target P41145 (Hs)
Ensembl Gene ENSG00000082556 (Hs), ENSMUSG00000025905 (Mm), ENSRNOG00000007647 (Rn)
Entrez Gene 4986 (Hs), 18387 (Mm), 29335 (Rn)
Human Protein Atlas ENSG00000082556 (Hs)
KEGG Gene hsa:4986 (Hs), mmu:18387 (Mm), rno:29335 (Rn)
OMIM 165196 (Hs)
Pharos P41145 (Hs)
RefSeq Nucleotide NM_000912 (Hs), NM_011011 (Mm), NM_017167 (Rn)
RefSeq Protein NP_000903 (Hs), NP_035141 (Mm), NP_058863 (Rn)
SynPHARM 83653 (in complex with JDTic)
83652 (in complex with JDTic)
UniProtKB P41145 (Hs), P33534 (Mm), P34975 (Rn)
Wikipedia OPRK1 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Structure of the human kappa opioid receptor in complex with JDTic
PDB Id:  4DJH
Ligand:  JDTic
Resolution:  2.9Å
Species:  Human
References:  127
Image of receptor 3D structure from RCSB PDB
Description:  Structure of the Nanobody-Stabilized Active State of the Kappa Opioid Receptor
PDB Id:  6B73
Ligand:  MP1104
Resolution:  3.1Å
Species:  Human
References:  15
Natural/Endogenous Ligands Click here for help
big dynorphin {Sp: Human, Mouse, Rat}
dynorphin A-(1-13) {Sp: Human, Mouse, Rat}
dynorphin A {Sp: Human, Mouse, Rat}
dynorphin A-(1-8) {Sp: Human, Mouse, Rat}
dynorphin B {Sp: Human, Mouse, Rat}
β-endorphin {Sp: Human} , β-endorphin {Sp: Mouse} , β-endorphin {Sp: Rat}
[Leu]enkephalin {Sp: Human, Mouse, Rat}
[Met]enkephalin {Sp: Human, Mouse, Rat}
α-neoendorphin {Sp: Human, Mouse, Rat}
β-neoendorphin {Sp: Human, Mouse, Rat}
Comments: Dynorphin A and big dynorphin are the highest potency endogenous ligands
Principal endogenous agonists (Human)
big dynorphin (PDYN, P01213), dynorphin A (PDYN, P01213)

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Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
nalfurafine Small molecule or natural product Ligand has a PDB structure Hs Full agonist 10.1 pKd 124
⤷ pKd 10.1 [124]
ethylketocyclazocine Small molecule or natural product Click here for species-specific activity table Hs Full agonist 9.4 pKd 116,136
⤷ pKd 9.4 [116,136]
enadoline Small molecule or natural product Hs Full agonist 8.6 – 9.2 pKd 35
⤷ pKd 8.6 – 9.2 [35]
[3H]U69593 Small molecule or natural product Ligand is labelled Ligand is radioactive Hs Full agonist 8.7 – 8.8 pKd 51,82,103
⤷ pKd 8.7 – 8.8 (Kd 2x10-9 – 1.6x10-9 M) [51,82,103]
(-)-bremazocine Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 10.5 pKi 116
⤷ pKi 10.5 [116]
ICI-199441 Small molecule or natural product Click here for species-specific activity table Hs Agonist 10.4 pKi 50
⤷ pKi 10.4 (Ki 4x10-11 M) [50]
Description: Displacement of [3H]diprenorphine from human κ opioid receptor
dynorphin A {Sp: Human, Mouse, Rat} Peptide Ligand is endogenous in the given species Rn Full agonist 10.0 – 10.3 pKi 59,67
⤷ pKi 10.0 – 10.3 [59,67]
(-)-cyclazocine Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 10.0 pKi 116
⤷ pKi 10.0 [116]
ethylketocyclazocine Small molecule or natural product Click here for species-specific activity table Hs Full agonist 10.0 pKi 116
⤷ pKi 10.0 [116]
dynorphin A-(1-13) {Sp: Human, Mouse, Rat} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 9.3 – 10.7 pKi 82,116
⤷ pKi 9.3 – 10.7 [82,116]
butorphanol Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Partial agonist 9.9 pKi 24
⤷ pKi 9.9 (Ki 1.2x10-10 M) [24]
Description: Displacement of [3H]U69593 from human κ opioid receptor expressed in CHO cells.
dynorphin A-(1-13) {Sp: Human, Mouse, Rat} Peptide Ligand is endogenous in the given species Rn Full agonist 9.9 pKi 67
⤷ pKi 9.9 [67]
dynorphin-(1-11) Peptide Click here for species-specific activity table Hs Full agonist 9.7 pKi 116
⤷ pKi 9.7 [116]
etorphine Small molecule or natural product Click here for species-specific activity table Hs Full agonist 9.7 pKi 116
⤷ pKi 9.7 [116]
GR 89696 Small molecule or natural product Hs Full agonist 9.7 pKi 89
⤷ pKi 9.7 [89]
enadoline Small molecule or natural product Hs Full agonist 9.6 pKi 40,74
⤷ pKi 9.6 [40,74]
probe 1.1 [PMID: 24187130] Small molecule or natural product Hs Agonist 9.6 pKi 134
⤷ pKi 9.6 (Ki 2.5x10-10 M) [134]
dynorphin A {Sp: Human, Mouse, Rat} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 8.3 – 10.8 pKi 82,103,116,135-136
⤷ pKi 8.3 – 10.8 [82,103,116,135-136]
dynorphin B {Sp: Human, Mouse, Rat} Peptide Ligand is endogenous in the given species Rn Full agonist 9.5 pKi 67
⤷ pKi 9.5 [67]
U69593 Small molecule or natural product Hs Full agonist 9.5 pKi 51,116
⤷ pKi 9.5 [51,116]
naloxone benzoylhydrazone Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 9.5 pKi 116
⤷ pKi 9.5 [116]
MP1104 Small molecule or natural product Hs Agonist 9.5 pKi 15
⤷ pKi 9.5 (Ki 3.3x10-10 M) [15]
probe 2.1 [PMID: 24187130] Small molecule or natural product Hs Agonist 9.5 pKi 134
⤷ pKi 9.5 (Ki 3.5x10-10 M) [134]
α-neoendorphin {Sp: Human, Mouse, Rat} Peptide Ligand is endogenous in the given species Rn Full agonist 8.9 – 10.0 pKi 59,67
⤷ pKi 8.9 – 10.0 [59,67]
HS665 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Full agonist 9.3 pKi 108
⤷ pKi 9.3 (Ki 4.9x10-10 M) [108]
α-neoendorphin {Sp: Human, Mouse, Rat} Peptide Ligand is endogenous in the given species Hs Full agonist 8.3 – 10.2 pKi 103,135
⤷ pKi 8.3 – 10.2 [103,135]
β-neoendorphin {Sp: Human, Mouse, Rat} Peptide Ligand is endogenous in the given species Rn Full agonist 9.1 pKi 67
⤷ pKi 9.1 [67]
E2078 Peptide Hs Full agonist 9.1 pKi 90
⤷ pKi 9.1 [90]
dynorphin B {Sp: Human, Mouse, Rat} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Partial agonist 8.1 – 9.9 pKi 82,103,116
⤷ pKi 8.1 – 9.9 [82,103,116]
spiradoline Small molecule or natural product Rn Full agonist 9.0 pKi 16
⤷ pKi 9.0 [16]
asimadoline Small molecule or natural product Immunopharmacology Ligand Cp Agonist 9.0 pKi 30
⤷ pKi 9.0 (Ki 1x10-9 M) [30]
Description: Displacement of [3H]- 69593 from K opioid receptors from guinea pig cerebellum.
dynorphin A-(1-8) {Sp: Human, Mouse, Rat} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Full agonist 8.0 – 9.9 pKi 82,103,116,129
⤷ pKi 8.0 – 9.9 [82,103,116,129]
ethylketocyclazocine Small molecule or natural product Rn Full agonist 8.8 pKi 67
⤷ pKi 8.8 [67]
E2078 Peptide Rn Full agonist 8.8 pKi 67
⤷ pKi 8.8 [67]
ICI 204448 Small molecule or natural product Rn Full agonist 8.8 pKi 16
⤷ pKi 8.8 [16]
tifluadom Small molecule or natural product Hs Full agonist 8.8 pKi 136
⤷ pKi 8.8 [136]
U50488 Small molecule or natural product Hs Agonist 7.8 – 9.7 pKi 14,82,103,116,123,135-136
⤷ pKi 7.8 – 9.7 [14,82,103,116,123,135-136]
cebranopadol Small molecule or natural product Click here for species-specific activity table Hs Agonist 8.6 pKi 60
⤷ pKi 8.6 (Ki 2.6x10-9 M) [60]
Description: Radioligand binding assay
hydromorphone Small molecule or natural product Approved drug Click here for species-specific activity table Hs Agonist 8.6 pKi 125
⤷ pKi 8.6 (Ki 2.8x10-9 M) [125]
nalorphine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Partial agonist 7.9 – 9.1 pKi 116,136
⤷ pKi 7.9 – 9.1 [116,136]
U50488 Small molecule or natural product Rn Partial agonist 8.2 – 8.7 pKi 16,59,67
⤷ pKi 8.2 – 8.7 [16,59,67]
U69593 Small molecule or natural product Rn Full agonist 8.0 – 8.7 pKi 16,67
⤷ pKi 8.0 – 8.7 [16,67]
salvinorin A Small molecule or natural product Hs Full agonist 7.8 – 8.7 pKi 11,94
⤷ pKi 7.8 – 8.7 [11,94]
BU08028 Small molecule or natural product Click here for species-specific activity table Hs Agonist 8.3 pKi 44
⤷ pKi 8.3 (Ki 5.63x10-9 M) [44]
compound 3 [PMID: 23134120] Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 8.2 pKi 108
⤷ pKi 8.2 (Ki 5.9x10-9 M) [108]
(-)-pentazocine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Partial agonist 7.8 – 8.6 pKi 116,136
⤷ pKi 7.8 – 8.6 [116,136]
β-neoendorphin {Sp: Human, Mouse, Rat} Peptide Ligand is endogenous in the given species Hs Full agonist 7.9 pKi 103
⤷ pKi 7.9 [103]
tramadol Small molecule or natural product Approved drug Click here for species-specific activity table Hs Agonist 7.8 pKi 125
⤷ pKi 7.8 (Ki 1.4x10-8 M) [125]
Description: Displacement of the kappa agonist U69593 from the kappa receptor expressed in CHO cells.
normorphine Small molecule or natural product Click here for species-specific activity table Hs Full agonist 7.8 pKi 116
⤷ pKi 7.8 [116]
ADL5747 Small molecule or natural product Click here for species-specific activity table Hs Agonist 7.6 pKi 56
⤷ pKi 7.6 (Ki 2.5x10-8 M) [56]
BW373U86 Small molecule or natural product Click here for species-specific activity table Rn Agonist 7.5 pKi 12
⤷ pKi 7.5 (Ki 3.4x10-8 M) [12]
nalbuphine Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Full agonist 7.4 – 7.5 pKi 136
⤷ pKi 7.4 – 7.5 [136]
ADL5859 Small molecule or natural product Click here for species-specific activity table Hs Agonist 7.4 pKi 55
⤷ pKi 7.4 (Ki 3.7x10-8 M) [55]
carfentanil Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Cp Agonist 7.4 pKi 17
⤷ pKi 7.4 (Ki 4.31x10-8 M) [17]
Description: Binding affinity- displacement of [3H]U69593 in guinea pig whole brain
morphine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Partial agonist 7.3 pKi 116
⤷ pKi 7.3 [116]
cebranopadol Small molecule or natural product Click here for species-specific activity table Rn Agonist 7.2 pKi 60
⤷ pKi 7.2 (Ki 6.4x10-8 M) [60]
Description: Radioligand binding assay
β-endorphin {Sp: Human} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Hs Partial agonist 6.3 – 7.9 pKi 103,116
⤷ pKi 6.3 – 7.9 [103,116]
dihydromorphine Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 7.1 pKi 116
⤷ pKi 7.1 [116]
fentanyl Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Partial agonist 7.1 pKi 116
⤷ pKi 7.1 [116]
etonitazene Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 6.9 pKi 116
⤷ pKi 6.9 [116]
BW373U86 Small molecule or natural product Click here for species-specific activity table Hs Agonist 6.9 pKi 55
⤷ pKi 6.9 (Ki 1.3x10-7 M) [55]
SCH221510 Small molecule or natural product Click here for species-specific activity table Hs Agonist 6.9 pKi 121
⤷ pKi 6.9 (Ki 1.31x10-7 M) [121]
Description: Radioligand binding assay
morphine Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Rn Partial agonist 6.7 – 7.0 pKi 16,67
⤷ pKi 6.7 – 7.0 [16,67]
β-endorphin {Sp: Human} Peptide Click here for species-specific activity table Rn Full agonist 6.8 pKi 67
⤷ pKi 6.8 [67]
UFP-512 Small molecule or natural product Click here for species-specific activity table Hs Agonist 6.7 pKi 122
⤷ pKi 6.7 [122]
Description: Measuring displacement of [3H]-diprenorphine in vitro
hydrocodone Small molecule or natural product Approved drug Click here for species-specific activity table Hs Agonist 6.6 pKi 75
⤷ pKi 6.6 (Ki 2.6x10-7 M) [75]
(-)-methadone Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 6.5 pKi 116
⤷ pKi 6.5 [116]
DAMGO Peptide Click here for species-specific activity table Hs Partial agonist 6.5 pKi 116
⤷ pKi 6.5 [116]
SR16835 Small molecule or natural product Click here for species-specific activity table Hs Agonist 6.2 pKi 117
⤷ pKi 6.2 (Ki 6.813x10-7 M) [117]
Description: Radioligand binding assay
bilorphin Small molecule or natural product Click here for species-specific activity table Hs Agonist 6.1 pKi 21
⤷ pKi 6.1 (Ki 7.7x10-7 M) [21]
[Leu]enkephalin {Sp: Human, Mouse, Rat} Peptide Ligand is endogenous in the given species Rn Full agonist 6.0 pKi 67
⤷ pKi 6.0 [67]
[Met]enkephalin {Sp: Human, Mouse, Rat} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Immunopharmacology Ligand Rn Full agonist 6.0 pKi 67
⤷ pKi 6.0 [67]
DAMGO Peptide Click here for species-specific activity table Rn Partial agonist 5.9 pKi 67
⤷ pKi 5.9 [67]
difelikefalin Peptide Approved drug Immunopharmacology Ligand Mm Agonist 10.3 pEC50 99
⤷ pEC50 10.3 (EC50 4.8x10-11 M) [99]
difelikefalin Peptide Approved drug Primary target of this compound Immunopharmacology Ligand Hs Agonist 9.8 pEC50 99
⤷ pEC50 9.8 (EC50 1.6x10-10 M) [99]
HS665 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Full agonist 8.4 pEC50 108
⤷ pEC50 8.4 (EC50 3.62x10-9 M) [108]
Description: Measuring stimulation of [35S]GTPγS binding.
compound 3 [PMID: 23134120] Small molecule or natural product Click here for species-specific activity table Hs Partial agonist 7.5 pEC50 108
⤷ pEC50 7.5 (EC50 3.5x10-8 M) [108]
Description: Measuring stimulation of [35S]GTPγS binding.
probe 1.1 [PMID: 24187130] Small molecule or natural product Hs Biased agonist 5.4 – 7.5 pEC50 134
⤷ pEC50 7.5 (EC50 3.1x10-8 M) [134]
Description: Measuring [35S]GTPγS binding
pEC50 5.4 (EC50 4.129x10-6 M) [134]
Description: Measuring βarrestin2 recruitment
probe 2.1 [PMID: 24187130] Small molecule or natural product Hs Biased agonist <5.0 – 7.1 pEC50 134
⤷ pEC50 7.1 (EC50 8.47x10-8 M) [134]
Description: Measuring [35S]GTPγS binding
pEC50 <5.0 (EC50 >1x10-5 M) [134]
Description: Measuring βarrestin2 recruitment
α-neoendorphin {Sp: Human, Mouse, Rat} Peptide Click here for species-specific activity table Ligand is endogenous in the given species Mm Full agonist 10.0 pIC50 128
⤷ pIC50 10.0 [128]
dynorphin B {Sp: Human, Mouse, Rat} Peptide Ligand is endogenous in the given species Mm Full agonist 10.0 pIC50 128
⤷ pIC50 10.0 [128]
dynorphin A-(1-8) {Sp: Human, Mouse, Rat} Peptide Ligand is endogenous in the given species Mm Full agonist 9.7 pIC50 128
⤷ pIC50 9.7 [128]
[D-Ala2,F5,Phe4]dynorphin-(1-17)-NH2 Peptide Mm Full agonist 9.7 pIC50 128
⤷ pIC50 9.7 [128]
dynorphin-(1-17)-NH2 Peptide Mm Full agonist 9.7 pIC50 128
⤷ pIC50 9.7 [128]
(-)-bremazocine Small molecule or natural product Mm Full agonist 9.5 pIC50 128
⤷ pIC50 9.5 [128]
dynorphin A {Sp: Human, Mouse, Rat} Peptide Ligand is endogenous in the given species Mm Full agonist 9.4 pIC50 128
⤷ pIC50 9.4 [128]
[Met5]dynorphin-(1-17) Peptide Mm Full agonist 9.2 pIC50 128
⤷ pIC50 9.2 [128]
ethylketocyclazocine Small molecule or natural product Click here for species-specific activity table Mm Full agonist 9.0 pIC50 128
⤷ pIC50 9.0 [128]
U50488 Small molecule or natural product Mm Partial agonist 9.0 pIC50 128
⤷ pIC50 9.0 [128]
spiradoline Small molecule or natural product Mm Full agonist 9.0 pIC50 128
⤷ pIC50 9.0 [128]
U69593 Small molecule or natural product Mm Full agonist 8.6 pIC50 128
⤷ pIC50 8.6 [128]
ICI 204448 Small molecule or natural product Mm Full agonist 8.2 pIC50 128
⤷ pIC50 8.2 [128]
[D-Ala2,F5,Phe4]dynorphin-(1-13)-NH2 Peptide Mm Full agonist 7.7 pIC50 128
⤷ pIC50 7.7 [128]
β-endorphin {Sp: Human} Peptide Click here for species-specific activity table Mm Partial agonist 7.4 pIC50 128
⤷ pIC50 7.4 [128]
nalbuphine Small molecule or natural product Approved drug Mm Full agonist 7.4 pIC50 128
⤷ pIC50 7.4 [128]
pethidine Small molecule or natural product Approved drug Click here for species-specific activity table Hs Agonist 5.6 pIC50 87
⤷ pIC50 5.6 (IC50 2.37x10-6 M) [87]
AR-M1000390 Small molecule or natural product Click here for species-specific activity table Hs Agonist 5.1 pIC50 4
⤷ pIC50 5.1 (IC50 7.47x10-6 M) [4]
[3H]enadoline Small molecule or natural product Ligand is labelled Ligand is radioactive Hs Full agonist - - 104
⤷ [104]
View species-specific agonist tables
Agonist Comments
Ki values were determined in the absence of Na+ and GDP, except TRK820.

Discrimination of full or partial agonism is very dependent on the level of receptor expression and on the assay used to monitor agonist effects. Many agents may behave as full agonists or potent partial agonists in cell lines expressing cloned receptors in high concentration, but in other environments they may show only weak agonist activity. The identification of agonist activity in the table is largely based on the ability to stimulate GTPγS binding in cell lines expressing cloned human kappa receptors. Agents giving 85% or greater stimulation than that given by U69593 have been characterized as Full Agonists [116].

κ opioid receptors have been divided into several different subtypes, mainly on the basis of [3H]agonist binding assays. Generally 2 subtypes are recognised: κ1 and κ2. The benzeneacetamides and peptides are considered κ1 agonists and the benzomorphans bind to κ1 and κ2. However, there is only one gene product and the subtypes are considered putative.

Selective κ agonists are of several structural types. All have high affinity for the κ receptor and are full agonists.

We have tagged the μ receptor as the primary drug target for hydrocodone based on this drug having the highest affinity at this receptor compared to the κ and δ receptors [75]. Similarly, we have tagged the μ receptor as the primary target of the drug hydromorphone [125].
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
LY2456302 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Antagonist 9.1 pKB 93
⤷ pKB 9.1 (KB 8.13x10-10 M) [93]
Description: Measuring inhibition of agonist-induced [35S]GTPγS binding in vitro.
zyklophin Peptide Primary target of this compound Click here for species-specific activity table Hs Antagonist 7.1 pKB 81
⤷ pKB 7.1 (KB 8.39x10-8 M) [81]
Description: Schild analysis of zyklophin vs. Dynorphin A-(1-13)NH2
[3H]diprenorphine Small molecule or natural product Click here for species-specific activity table Ligand is labelled Ligand is radioactive Hs Antagonist 9.1 pKd 3,103
⤷ pKd 9.1 (Kd 7.94x10-10 M) [3,103]
nor-binaltorphimine Small molecule or natural product Rn Antagonist 9.6 – 10.7 pKi 16,59,67
⤷ pKi 9.6 – 10.7 [16,59,67]
JDTic Small molecule or natural product Primary target of this compound Ligand has a PDB structure Hs Antagonist 9.0 – 11.2 pKi 71,114,131
⤷ pKi 11.2 (Ki 6x10-12 M) [114]
Description: Measuring antagonism of U50,488-induced [35S]GTPγS binding
pKi 9.0 – 9.4 (Ki 1x10-9 – 3.98x10-10 M) [71,114,131]
nor-binaltorphimine Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.9 – 11.0 pKi 82,86,103,116,135-136
⤷ pKi 8.9 – 11.0 [82,86,103,116,135-136]
5'-guanidinonaltrindole Small molecule or natural product Hs Antagonist 9.7 – 9.9 pKi 41,82,110
⤷ pKi 9.7 – 9.9 [41,82,110]
β-FNA Small molecule or natural product Click here for species-specific activity table Hs Antagonist 9.7 pKi 116
⤷ pKi 9.7 [116]
quadazocine Small molecule or natural product Click here for species-specific activity table Hs Antagonist 9.7 pKi 116
⤷ pKi 9.7 [116]
diprenorphine Small molecule or natural product Click here for species-specific activity table Hs Antagonist 9.6 – 9.7 pKi 82,116,135-136
⤷ pKi 9.6 – 9.7 [82,116,135-136]
buprenorphine Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 9.1 – 10.2 pKi 116,136
⤷ pKi 9.1 – 10.2 [116,136]
samidorphan Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 9.6 pKi 126
⤷ pKi 9.6 (Ki 2.3x10-10 M) [126]
nalmefene Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 9.5 pKi 116
⤷ pKi 9.5 [116]
LY2456302 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Antagonist 9.1 pKi 93
⤷ pKi 9.1 (Ki 8.07x10-10 M) [93]
AT-076 Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.9 pKi 116,131
⤷ pKi 8.9 (Ki 1.14x10-9 M) [116,131]
Description: Radioligand binding assay
naltrexone Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 8.4 – 9.4 pKi 82,103,116
⤷ pKi 8.4 – 9.4 [82,103,116]
BNTX Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.4 pKi 116
⤷ pKi 8.4 [116]
naltriben Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 8.4 pKi 116
⤷ pKi 8.4 [116]
NFP Small molecule or natural product Click here for species-specific activity table Hs Antagonist 8.3 pKi 133
⤷ pKi 8.3 (Ki 4.8x10-9 M) [133]
Description: In a competitive radioligand membrane binding assay measuring displacement of [3H]diprenorphine by NFP from κ receptor expressed in CHO cells.
methylnaltrexone Small molecule or natural product Approved drug Click here for species-specific activity table Hs Antagonist 8.2 pKi 125
⤷ pKi 8.2 (Ki 6.3x10-9 M) [125]
naloxone Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Hs Antagonist 7.6 – 8.6 pKi 82,103,116,135-136
⤷ pKi 7.6 – 8.6 [82,103,116,135-136]
naltrindole Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 8.0 pKi 116
⤷ pKi 8.0 [116]
naltrindole Small molecule or natural product Ligand has a PDB structure Rn Antagonist 7.9 pKi 59
⤷ pKi 7.9 [59]
naloxone Small molecule or natural product Approved drug Rn Antagonist 7.7 – 8.0 pKi 16,59,67
⤷ pKi 7.7 – 8.0 [16,59,67]
zyklophin Peptide Primary target of this compound Click here for species-specific activity table Hs Antagonist 7.5 pKi 81
⤷ pKi 7.5 (Ki 3.03x10-8 M) [81]
alvimopan Small molecule or natural product Approved drug Click here for species-specific activity table Ligand has a PDB structure Hs Antagonist 7.0 pKi 54
⤷ pKi 7.0 (Ki 1x10-7 M) [54]
(+)-naloxone Small molecule or natural product Rn Antagonist 4.7 pKi 67
⤷ pKi 4.7 [67]
naltrexone Small molecule or natural product Approved drug Click here for species-specific activity table Mm Antagonist 9.2 pIC50 128
⤷ pIC50 9.2 [128]
NMRA-140 Small molecule or natural product Primary target of this compound Click here for species-specific activity table Hs Antagonist 9.1 pIC50 32
⤷ pIC50 9.1 (IC50 8x10-10 M) [32]
nor-binaltorphimine Small molecule or natural product Click here for species-specific activity table Mm Antagonist 8.9 pIC50 128
⤷ pIC50 8.9 [128]
naloxone Small molecule or natural product Approved drug Click here for species-specific activity table Mm Antagonist 8.3 pIC50 128
⤷ pIC50 8.3 [128]
naltrindole Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Mm Antagonist 7.4 pIC50 128
⤷ pIC50 7.4 [128]
View species-specific antagonist tables
Allosteric Modulator Comments
Although no small molecules are considered direct allosteric regulators of κ opioid receptors, a number of proteins such as G protein-coupled receptor kinases, β-arrestins and G proteins clearly regulate receptor affinities and function. Furthermore, sodium and guanine nucleotides can modify the functional κ receptor complex and G protein interaction. Also, other G protein-coupled receptors appear to be able to form heterodimers with κ receptors, potentially modifying κ opioid receptor activity.
Other Binding Ligands
Key to terms and symbols Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 16 [PMID: 31498617] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Binding 4.9 pKi 88
⤷ pKi 4.9 (Ki 1.21x10-5 M) [88]
Description: Receptor binding in a radioligand displacement assay using [3H]U-69,593 as tracer.
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family Adenylyl cyclase inhibition
Potassium channel
Calcium channel
References:  6,31,34,46,53,69,98,111
Secondary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family
G12/G13 family 		Adenylyl cyclase inhibition
Phospholipase C stimulation
Other - See Comments
Comments:  Activation of κ opioid receptors stimulates p42/p44 MAP kinase via βγ subunits of Gi/o proteins [10].
κ opioid receptors interact with NHERF-1/EBP50 to stimulate Na+/H+ exchange independent of Gi/o proteins [39].
References:  10,39,52,58,72,119
Tissue Distribution Click here for help
CNS: olfactory bulb, nucleus accumbens, caudate nucleus, putamen, temporal cortex, parietal cortex, thalamic nuclei > amygdala, occipital cortex, frontal cortex, hypothalamus, ventral tegmental area, cerebellar cortex > hippocampus, corpus mamillare, locus coeruleus, pituitary, spinal cord > globus pallidus, substantia nigra, superior colliculus, inferior colliculus, olivary nucleus.
Species:  Human
Technique:  RT-PCR.
References:  103
Skin.
Species:  Human
Technique:  RT-PCR and Immunohistochemistry.
References:  96
Immune cells.
Species:  Human
Technique:  RT-PCR.
References:  25
CNS: amygdala, caudate nucleus, hypothalamus, subthalamic nucleus > hippocampus, thalamus > substantia nigra, corpus callosum.
Species:  Human
Technique:  Northern blotting.
References:  135
Intestine.
Species:  Mouse
Technique:  RT-PCR.
References:  85
CNS: claustrum, nucleus accumbens, endopiriform nucleus, ventral pallidum, preoptic area, fundus striati, hypothalamus, substantia nigra.
Species:  Mouse
Technique:  Radioligand binding.
References:  45
CNS: olfactory tubercle, endopiriform nucleus, ventral pallidum, hypothalamus, deep cortical layers, claustrum.
Species:  Mouse
Technique:  Radioligand binding.
References:  45
Pregnant uterus.
Species:  Mouse
Technique:  in situ hybridisation.
References:  138
Ear: cochlea.
Species:  Rat
Technique:  RT-PCR and immunocytochemistry.
References:  42
CNS: amygdala, olfactory tubercle, nucleus accumbens, caudate putamen, medial preoptic area, hypothalamus, median eminence, periventricular thalamus, interpeduncular nucleus.
Species:  Rat
Technique:  Radioligand binding.
References:  64
κ1: CNS: claustrum, endopiriform nucleus, caudate putamen, nucleus accumbens, midline nuclear group of the thalamus, superficial grey layer of the superior colliculus, central grey.
κ2: CNS: caudate putamen, nucleus accumbens, amygdala, thalamus, interpeduncular nuclei.
Species:  Rat
Technique:  Radioligand binding.
References:  120
CNS: ventral forebrain, hypothalamus, thalamus, posterior pituitary, and midbrain. Primarily postsynaptic membranes.
Species:  Rat
Technique:  Immunohistochemistry.
References:  5
CNS: hippocampus, dentate gyrus, hypothalamic and thalamic nuclei, cortex, caudate putamen, olfactory tubercle, nucleus accumbens
Species:  Rat
Technique:  in situ hybridisation.
References:  27
CNS: κ receptors only represent a small percentage of opioid receptors in the superficial layers (I and II) of the dorsal horn of the spinal cord.
Species:  Rat
Technique:  Radioligand binding.
References:  9
CNS: telencephalon, diencephalon > mesencephalon, metencephalon.
Species:  Rat
Technique:  Radioligand binding.
References:  78
CNS: nucleus accumbens, pyramidal and molecular layers of the hippocampus, granular cell layer of the dentate gyrus, midline nuclei of the thalamus, hindbrain regions > striatum.
Species:  Rat
Technique:  Radioligand binding.
References:  113
Tissue Distribution Comments
κ opioid receptors show a fairly widespread distribution although quantitatively they represent only a small percentage of the total opioid receptors in the brain. This contrasts with the guinea-pig brain, where κ opioid receptor expression is far more abundant. In all species, the early receptor autoradiography was carried out with low selectivity ligands such as [3H]ethylketocycazocine and [3H]bremazocine and their cross labelling of μ and δ receptors was supressed by the use of excess cold ligands to displace their binding to μ and δ opioid sites. Since the late 1980s highly selective κ opioid receptor ligands such as [3H]U69,593 and [3H]CI-977 have been used and the distribution is more restrictive when these ligands are employed.

For a review of κ opioid receptor expression in the rat see [63].
Expression Datasets Click here for help

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays Click here for help
Measurement of Ca2+ conductance, using a whole cell voltage clamp, in PC-12 cells transfected with the mouse κ receptor.
Species:  Mouse
Tissue:  PC-12 cells.
Response measured:  Increase in K+ conductance and decrease in Ca2+ conductance.
References:  111
Measurement of musculature contraction of sections of mouse vas deferens following stimulation of the intramural nerves.
Species:  Mouse
Tissue:  Vas deferens.
Response measured:  Inhibition of electrically-evoked contractions.
References:  18
Measurement of K+ conductance, using a 2 electrode voltage clamp, in Xenopus oocytes transfected with the rat κ receptor and Kir3 channel.
Species:  Rat
Tissue:  Xenopus oocytes.
Response measured:  Increase in K+ conductance.
References:  34
Measurement of cAMP levels in R1.1 murine thymoma cells endogenously expressing the κ receptor.
Species:  Mouse
Tissue:  R1.1 murine thymoma cells.
Response measured:  Inhibition of cAMP accumulation.
References:  53
Measurement of cAMP levels in CHO cells transfected with the rat κ receptor.
Species:  Rat
Tissue:  CHO cells.
Response measured:  Inhibition of cAMP accumulation.
References:  7
Measurement of cAMP levels in PC-12 cells transfected with the mouse κ receptor.
Species:  Mouse
Tissue:  PC-12 cells.
Response measured:  Inhibition of cAMP accumulation.
References:  111
Measurement of cAMP levels in COS-7 cells transfected with the rat κ receptor.
Species:  Rat
Tissue:  COS-7 cells.
Response measured:  Inhibition of cAMP accumulation.
References:  16
Measurement of cAMP levels in CHO cells transfected with the human κ receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  Inhibition of cAMP accumulation.
References:  137
Measurement of [35S]GTPγS binding in CHO cells transfected with the human κ receptor.
Species:  Human
Tissue:  CHO cells.
Response measured:  [35S]GTPγS binding.
References:  136
Physiological Functions Click here for help
Sedative and sensorimotor effects in rats.
Species:  Rat
Tissue:  In vivo.
References:  118,123
Water diuresis, potentially by modulation of vasopressin.
Species:  Human
Tissue:  In vivo.
References:  79,84,91
Water diuresis, potentially by modulation of vasopressin.
Species:  Rat
Tissue:  In vivo.
References:  57,106,123
Water diuresis, potentially by modulation of vasopressin.
Species:  Mouse
Tissue:  In vivo.
References:  123
Neuroendocrine effects: stimulation of prolactin release, probably by modulation of the tuberoinfundibular dopamine system.
Species:  Human
Tissue:  In vivo.
References:  48,83
Neuroendocrine effects: stimulation of prolactin release, probably by modulation of the tuberoinfundibular dopamine system.
Species:  Rat
Tissue:  In vivo.
References:  23,49
Sedative and sensorimotor effects in mice.
Species:  Mouse
Tissue:  In vivo.
References:  118,123
Sedative and interoceptive effects in humans (such as psychotomimetic, dysphoric and potentially hallucinogenic).
Species:  Human
Tissue:  In vivo.
References:  92
Modulation of dopaminergic function.
Species:  Human
Tissue:  In vivo.
References:  130
Modulation of dopaminergic function. This may be related to the κ agonist effects on hedonic states (such as causing place aversion in rodents), as well as the blockade of the reinforcing, locomotor stimulant and neurobiological effects of psychostimulants such as cocaine.
Species:  Rat
Tissue:  In vivo.
References:  22,28,62,102,107
Modulation of dopaminergic function. This may be related to the κ agonist effects on hedonic states (such as causing place aversion in rodents), as well as the blockade of the reinforcing, locomotor stimulant and neurobiological effects of psychostimulants such as cocaine.
Species:  Mouse
Tissue:  In vivo.
References:  132
Immune changes have been observed in immune cells in peripheral tissues.
Species:  Mouse
Tissue:  lymphoid cells.
References:  101,112
Immune changes have been observed in immune cells in central tissues.
Species:  Human
Tissue:  Microglial cells.
References:  13,66
Enhancement of food intake.
Species:  Rat
Tissue:  In vivo.
References:  70
Blockade of pruritus.
Species:  Mouse
Tissue:  In vivo.
References:  115
Blockade of pruritus.
Species:  Rat
Tissue:  In vivo.
References:  29
Body temperature regulation:
κ receptor activation induces hypothermia, blocked by selective κ receptor antagonists. The effect is centrally mediated, involving both oxidative metabolism and heat exchange.
Species:  Rat
Tissue:  In vivo.
References:  1,33
Antinociception: systemic administration.
Species:  Rat
Tissue:  In vivo.
References:  97,123
Antinociception: systemic administration.
Species:  Mouse
Tissue:  In vivo.
References:  73,123
Antinociception: systemic administration.
Species:  Human
Tissue:  In vivo.
References:  80
Peripheral antinociception.
Species:  Rat
Tissue:  In vivo.
References:  2,109
Attenuation of contractions induced by intestinal distension in the gastrointestinal tract.
Species:  Rat
Tissue:  In vivo.
References:  100
Stimulation of relief from abdominal pain and bloating.
Species:  Human
Tissue:  In vivo.
References:  19
Physiological Consequences of Altering Gene Expression Click here for help
κ receptor knockout mice exhibit increased in humoral responses to antigen challenge.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  26
κ opioid receptor knockout mice exhibit enhanced sensitivity to chemical visceral pain, abolished hypolocomotor, analgesic and aversive actions of the prototypic κ receptor agonist U50488H and attenuation of morphine withdrawl.
Species:  Mouse
Tissue: 
Technique:  Gene targeting in embryonic stem cells.
References:  105
Phenotypes, Alleles and Disease Models Click here for help Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Oprk1tm1Jep Oprk1tm1Jep/Oprk1tm1Jep
involves: C57BL/6		 MGI:97439  MP:0001462 abnormal avoidance learning behavior PMID: 19864633 
Oprk1tm1Kff Oprk1tm1Kff/Oprk1tm1Kff
involves: 129S2/SvPas * C57BL/6		 MGI:97439  MP:0001392 abnormal locomotor activity PMID: 9463367 
Oprk1tm1Kff Oprk1tm1Kff/Oprk1tm1Kff
involves: 129S2/SvPas * C57BL/6		 MGI:97439  MP:0001970 abnormal pain threshold PMID: 9463367 
Oprk1tm1Jep Oprk1tm1Jep/Oprk1tm1Jep
involves: 129S/SvEv * 129S6/SvEvTac * C57BL/6		 MGI:97439  MP:0001982 decreased chemically-elicited antinociception PMID: 16672569 
Oprk1tm1Kff Oprk1tm1Kff/Oprk1tm1Kff
involves: 129S2/SvPas * C57BL/6		 MGI:97439  MP:0000623 decreased salivation PMID: 9463367 
Oprk1tm1Jep Oprk1tm1Jep/Oprk1tm1Jep
Not Specified		 MGI:97439  MP:0009778 impaired behavioral response to anesthetic PMID: 11032994 
Oprk1tm1Kff Oprk1tm1Kff/Oprk1tm1Kff
involves: 129S2/SvPas * C57BL/6		 MGI:97439  MP:0009757 impaired behavioral response to morphine PMID: 9463367 
Oprk1tm1Kff Oprk1tm1Kff/Oprk1tm1Kff
involves: 129S2/SvPas * C57BL/6		 MGI:97439  MP:0001934 increased litter size PMID: 9463367 
Oprk1+|Oprk1tm1Kff Oprk1tm1Kff/Oprk1+
involves: 129S2/SvPas * C57BL/6		 MGI:97439  MP:0001934 increased litter size PMID: 9463367 
Biologically Significant Variant Comments
κ1 and κ2 receptor subtypes have been proposed based on in vivo pharmacology showing lack of cross-tolerance between U69,593 and bremazocine and differential antagonism by quadazocine and (-)UPHIT [36-38]. Receptor binding studies have led to suggestions of κ1, κ2 and κ3 subtypes [20,95]. However, only one κ receptor cDNA clone has been reported and no κ receptor variants have been characterised. Interaction between κ and δ receptors in transfected cells has been reported and suggested to result in κ2 subtype pharmacology [43]. Multiple active conformations of the κ receptor are likely to exist. κ receptor subtypes are likely due to interaction of receptor with other proteins or receptors at the level of neuronal circuitry, but not mRNA variants.

References

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