Delta Opioid receptor
Encyclopedia
The δ-opioid receptors, also known as delta opioid receptor or simply delta receptor, abbreviated DOR, is an opioid receptor
that has enkephalin
s as its endogenous ligands.
Evidence for whether delta agonists produce respiratory depression is mixed; high doses of the delta agonist peptide DPDPE produced respiratory depression in sheep, but in tests on mice the non-peptide delta agonist SNC-80 produced respiratory depression only at the very high dose of 40 mg/kg. In contrast both the peptide delta agonist Deltorphin II and the non-peptide delta agonist (+)-BW373U86 actually stimulated respiratory function and blocked the respiratory depressant effect of the potent mu-opioid agonist alfentanil
, without affecting pain relief. It thus seems likely that while delta opioid agonists can produce respiratory depression at very high doses, at lower doses they have the opposite effect, a fact that may make mixed mu/delta agonists such as DPI-3290 potentially very useful drugs that might be much safer than the mu agonists currently used for pain relief.
Of additional interest is the potential for delta agonists to be developed for use as a novel class of antidepressant
drugs, following robust evidence of both antidepressant effects and also upregulation of BDNF production in the brain in animal models of depression. These antidepressant effects have been linked to endogenous opioid peptides acting at delta and mu opioid receptors, and so can also be produced by enkephalinase inhibitors such as RB-101.
Recent work indicates that exogenous ligands that activate the delta receptors mimic the phenomenon known as ischemic preconditioning
. Experimentally, if short periods of transient ischemia
are induced the downstream tissues are robustly protected if longer-duration interruption of the blood supply is then effected. Opiate
s and opioid
s with delta activity mimic this effect. In the rat model introduction of delta active ligands results in significant cardioprotection.
However there are now several selective delta opioid agonists available, including peptides such as DPDPE and deltorphin II, and non-peptide drugs such as SNC-80
, the more potent (+)-BW373U86
, a newer drug DPI-287
, which does not produce the problems with convulsions seen with the earlier agents, and the mixed mu/delta agonist DPI-3290
, which is a much more potent analgesic than the more highly selective delta agonists. Selective antagonists for the delta receptor are also available, with the best known being the opiate derivative naltrindole
.
Non-peptides
Mitragyna Speciosa(aka Kratom
) Indole Agonists:
with beta-2 adrenergic receptor
s, arrestin beta 1
and GPRASP1
.
Opioid receptor
Opioid receptors are a group of G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors...
that has enkephalin
Enkephalin
An enkephalin is a pentapeptide involved in regulating nociception in the body. The enkephalins are termed endogenous ligands, or specifically endorphins, as they are internally derived and bind to the body's opioid receptors. Discovered in 1975, two forms of enkephalin were revealed, one...
s as its endogenous ligands.
Function
Activation of delta receptors produces some analgesia, although less than that of mu-opioid agonists. Many delta agonists may also cause seizures at high doses, although not all delta agonists produce this effect.Evidence for whether delta agonists produce respiratory depression is mixed; high doses of the delta agonist peptide DPDPE produced respiratory depression in sheep, but in tests on mice the non-peptide delta agonist SNC-80 produced respiratory depression only at the very high dose of 40 mg/kg. In contrast both the peptide delta agonist Deltorphin II and the non-peptide delta agonist (+)-BW373U86 actually stimulated respiratory function and blocked the respiratory depressant effect of the potent mu-opioid agonist alfentanil
Alfentanil
Alfentanil is a potent but short-acting synthetic opioid analgesic drug, used for anaesthesia in surgery. It is an analogue of fentanyl with around 1/4 the potency of fentanyl and around 1/3 of the duration of action, but with an onset of effects 4x faster than fentanyl...
, without affecting pain relief. It thus seems likely that while delta opioid agonists can produce respiratory depression at very high doses, at lower doses they have the opposite effect, a fact that may make mixed mu/delta agonists such as DPI-3290 potentially very useful drugs that might be much safer than the mu agonists currently used for pain relief.
Of additional interest is the potential for delta agonists to be developed for use as a novel class of antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
drugs, following robust evidence of both antidepressant effects and also upregulation of BDNF production in the brain in animal models of depression. These antidepressant effects have been linked to endogenous opioid peptides acting at delta and mu opioid receptors, and so can also be produced by enkephalinase inhibitors such as RB-101.
Recent work indicates that exogenous ligands that activate the delta receptors mimic the phenomenon known as ischemic preconditioning
Ischemic preconditioning
Ischemic preconditioning is an experimental technique for producing resistance to the loss of blood supply and, thus oxygen, to tissues of many types. IPC is an intrinsic process whereby repeated short episodes of ischaemia protect the myocardium against a subsequent ischaemic insult. It was first...
. Experimentally, if short periods of transient ischemia
Ischemia
In medicine, ischemia is a restriction in blood supply, generally due to factors in the blood vessels, with resultant damage or dysfunction of tissue. It may also be spelled ischaemia or ischæmia...
are induced the downstream tissues are robustly protected if longer-duration interruption of the blood supply is then effected. Opiate
Opiate
In medicine, the term opiate describes any of the narcotic opioid alkaloids found as natural products in the opium poppy plant.-Overview:Opiates are so named because they are constituents or derivatives of constituents found in opium, which is processed from the latex sap of the opium poppy,...
s and opioid
Opioid
An opioid is a psychoactive chemical that works by binding to opioid receptors, which are found principally in the central and peripheral nervous system and the gastrointestinal tract...
s with delta activity mimic this effect. In the rat model introduction of delta active ligands results in significant cardioprotection.
Ligands
Until comparatively recently, there were few pharmacological tools for the study of δ receptors. As a consequence, our understanding of their function is much more limited than those of the other opioid receptors for which selective ligands have long been available.However there are now several selective delta opioid agonists available, including peptides such as DPDPE and deltorphin II, and non-peptide drugs such as SNC-80
SNC-80
SNC-80 is an opioid analgesic drug used in scientific research. It was invented in 1994.SNC-80 was the first non-peptide drug developed that is a highly selective agonist for the δ-opioid receptor....
, the more potent (+)-BW373U86
BW373U86
BW373U86 is an opioid analgesic drug used in scientific research.BW373U86 is a selective agonist for the δ-opioid receptor, with approximately 15x stronger affinity for the δ-opioid than the μ-opioid receptor...
, a newer drug DPI-287
DPI-287
DPI-287 is a drug that is used in scientific research. It is a highly selective agonist for the δ-opioid receptor, which produces less convulsions than most drugs from this family. It has antidepressant effects....
, which does not produce the problems with convulsions seen with the earlier agents, and the mixed mu/delta agonist DPI-3290
DPI-3290
DPI-3290 was discoverd by Delta Pharmacutical and is a drug that is used in scientific research. It is a potent analgesic drug, which produces little respiratory depression....
, which is a much more potent analgesic than the more highly selective delta agonists. Selective antagonists for the delta receptor are also available, with the best known being the opiate derivative naltrindole
Naltrindole
Naltrindole is a highly potent, highly selective delta opioid receptor antagonist used in biomedical research.-Drug design:Since peptide compounds are unable to cross the blood brain barrier, researchers developed naltrindole to be a non-peptide antagonist analog of the delta-preferring endogenous...
.
Agonists
Peptides- Leu-enkephalinLeu-enkephalinLeu-enkephalin is an endogenous opioid peptide neurotransmitter with the amino acid sequence Tyr-Gly-Gly-Phe-Leu that is found naturally in the brains of many animals, including humans. It is one of the two forms of enkephalin; the other is met-enkephalin. The tyrosine residue at position 1 is...
- Met-enkephalinMet-enkephalin[Met]enkephalin, sometimes referred to as opioid growth factor , is a naturally-occurring, endogenous opioid peptide that has opioid effects of a relatively short duration. It is one of the two forms of enkephalin, the other being [leu]enkephalin...
- Deltorphins
Non-peptides
- 7-Spiroindanyloxymorphone7-Spiroindanyloxymorphone7-Spiroindanyloxymorphone is a drug which is used in scientific research. It is a selective δ-opioid agonist....
- N-Phenethyl-14-ethoxymetoponN-Phenethyl-14-ethoxymetoponN-Phenethyl-14-ethoxymetopon is a drug which is a derivative of metopon. It is a potent analgesic, around 60 times stronger than morphine and produces significantly less constipation....
- ADL-5859
- BU-48BU-48BU-48 is a drug which is used in scientific research. It is from the oripavine family, related to better known drugs such as etorphine and buprenorphine....
- SNC-80SNC-80SNC-80 is an opioid analgesic drug used in scientific research. It was invented in 1994.SNC-80 was the first non-peptide drug developed that is a highly selective agonist for the δ-opioid receptor....
- BW373U86BW373U86BW373U86 is an opioid analgesic drug used in scientific research.BW373U86 is a selective agonist for the δ-opioid receptor, with approximately 15x stronger affinity for the δ-opioid than the μ-opioid receptor...
- DPI-221DPI-221DPI-221 is a drug which is used in scientific research. It is a highly selective agonist for the δ-opioid receptor which produces less convulsions than most drugs from this family....
- DPI-287DPI-287DPI-287 is a drug that is used in scientific research. It is a highly selective agonist for the δ-opioid receptor, which produces less convulsions than most drugs from this family. It has antidepressant effects....
- DPI-3290DPI-3290DPI-3290 was discoverd by Delta Pharmacutical and is a drug that is used in scientific research. It is a potent analgesic drug, which produces little respiratory depression....
- TAN-67TAN-67TAN-67 is a drug which is used in scientific research, which is a potent and selective δ-opioid agonist, selective for the δ1 subtype. It has analgesic properties and induces dopamine release in the brain...
- RWJ-394,674RWJ-394,674RWJ-394674 is a drug which is used in scientific research. It is a potent, orally active analgesic drug, which produces little respiratory depression. RWJ-394674 itself is a potent and selective agonist for δ-opioid receptors, with a Ki of 0.24 nM at δ and 72 nM at μ...
- NorbuprenorphineNorbuprenorphineNorbuprenorphine is the primary active metabolite of buprenorphine. Norbuprenorphine acts as a μ-opioid, δ-opioid, and nociceptin receptor full agonist, as well as a κ-opioid receptor partial agonist. Norbuprenorphine crosses the blood-brain-barrier similarly to buprenorphine and likely contributes...
Mitragyna Speciosa(aka Kratom
Kratom
Kratom , Mitragyna speciosa, is a medicinal leaf harvested from a large tree in the Rubiaceae family native to Southeast Asia in the Indochina and Malesia floristic regions. The plant has been traditionally used for its medicinal properties.It was first formally documented by the Dutch colonial...
) Indole Agonists:
- MitragynineMitragynineMitragynine, an indole alkaloid, is the most abundant active alkaloid in the plant Mitragyna speciosa, commonly known as Kratom.-Pharmacology:...
- Mitragynine-pseudoindoxyl
Interactions
Delta opioid receptors have been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with beta-2 adrenergic receptor
Beta-2 adrenergic receptor
The beta-2 adrenergic receptor , also known as ADRB2, is a beta-adrenergic receptor, and also denotes the human gene encoding it.-Gene:The gene is intronless...
s, arrestin beta 1
Arrestin beta 1
Arrestin, beta 1, also known as ARRB1, is a protein which in humans is encoded by the ARRB1 gene.- Function :Members of arrestin/beta-arrestin protein family are thought to participate in agonist-mediated desensitization of G protein-coupled receptors and cause specific dampening of cellular...
and GPRASP1
GPRASP1 (gene)
G-protein coupled receptor-associated sorting protein 1 is a protein that in humans is encoded by the GPRASP1 gene.-Interactions:GPRASP1 has been shown to interact with Delta Opioid receptor.-Further reading:...
.