Δ-opioid receptor

Δ-opioid receptor

Opioid receptor, delta 1

Structure of the human delta-type opioid receptor with bound Naltrindole. PDB entry
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
Symbols  ; OPRD
External IDs IUPHAR: ChEMBL: GeneCards:
RNA expression pattern
Orthologs
Species Human Mouse
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UniProt
RefSeq (mRNA)
RefSeq (protein)
Location (UCSC)
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The δ-opioid receptor, also known as delta opioid receptor or simply delta receptor, abbreviated DOR, is an opioid receptor that has enkephalins as its endogenous ligands.[1]

Function

Activation of δ receptors produces some analgesia, although less than that of mu-opioid agonists.[2] Many δ agonists may also cause seizures at high doses, although not all δ agonists produce this effect.[3]

Evidence for whether δ agonists produce respiratory depression is mixed; high doses of the δ agonist peptide DPDPE produced respiratory depression in sheep,[4] but in tests on mice the non-peptide δ agonist SNC-80 produced respiratory depression only at the very high dose of 40 mg/kg.[5] In contrast both the peptide δ agonist Deltorphin II and the non-peptide δ agonist (+)-BW373U86 actually stimulated respiratory function and blocked the respiratory depressant effect of the potent μ-opioid agonist alfentanil, without affecting pain relief.[6] It thus seems likely that while δ opioid agonists can produce respiratory depression at very high doses, at lower doses they have the opposite effect, a fact that may make mixed μ/δ agonists such as DPI-3290 potentially very useful drugs that might be much safer than the μ agonists currently used for pain relief.

Of additional interest is the potential for δ agonists to be developed for use as a novel class of antidepressant drugs, following robust evidence of both antidepressant effects[7] and also upregulation of BDNF production in the brain in animal models of depression.[8] These antidepressant effects have been linked to endogenous opioid peptides acting at δ and μ opioid receptors,[9] and so can also be produced by enkephalinase inhibitors such as RB-101.[10]

Recent work indicates that exogenous ligands that activate the δ receptors mimic the phenomenon known as ischemic preconditioning.[11] 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. Opiates and opioids with δ activity mimic this effect. In the rat model, introduction of δ active ligands results in significant cardioprotection.[12]

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 δ opioid agonists available, including peptides such as DPDPE and deltorphin II, and non-peptide drugs such as SNC-80,[13] the more potent (+)-BW373U86,[14] a newer drug DPI-287, which does not produce the problems with convulsions seen with the earlier agents,[15] and the mixed μ/δ agonist DPI-3290, which is a much more potent analgesic than the more highly selective δ agonists.[16] Selective antagonists for the δ receptor are also available, with the best known being the opiate derivative naltrindole.[17]

Agonists

Peptides
Non-peptides

Mitragyna speciosa (kratom) indole derivatives:

Antagonists

Interactions

δ−opioid receptors have been shown to interact with β2 adrenergic receptors,[20] arrestin β1[21] and GPRASP1.[22]

References

  1. ^ Quock RM, Burkey TH, Varga E, Hosohata Y, Hosohata K, Cowell SM, Slate CA, Ehlert FJ, Roeske WR, Yamamura HI (1999). "The delta-opioid receptor: molecular pharmacology, signal transduction, and the determination of drug efficacy". Pharmacol. Rev. 51 (3): 503–32.  
  2. ^ Varga EV, Navratilova E, Stropova D, Jambrosic J, Roeske WR, Yamamura HI (2004). "Agonist-specific regulation of the delta-opioid receptor". Life Sci. 76 (6): 599–612.  
  3. ^ Jutkiewicz EM, Baladi MG, Folk JE, Rice KC, Woods JH (2006). "The convulsive and electroencephalographic changes produced by nonpeptidic delta-opioid agonists in rats: comparison with pentylenetetrazol". J. Pharmacol. Exp. Ther. 317 (3): 1337–48.  
  4. ^ Clapp JF, Kett A, Olariu N, Omoniyi AT, Wu D, Kim H, Szeto HH (1998). "Cardiovascular and metabolic responses to two receptor-selective opioid agonists in pregnant sheep". Am. J. Obstet. Gynecol. 178 (2): 397–401.  
  5. ^ Gallantine EL, Meert TF (2005). "A comparison of the antinociceptive and adverse effects of the mu-opioid agonist morphine and the delta-opioid agonist SNC80". Basic Clin. Pharmacol. Toxicol. 97 (1): 39–51.  
  6. ^ Su YF, McNutt RW, Chang KJ (1998). "Delta-opioid ligands reverse alfentanil-induced respiratory depression but not antinociception". J. Pharmacol. Exp. Ther. 287 (3): 815–23.  
  7. ^ Broom DC, Jutkiewicz EM, Rice KC, Traynor JR, Woods JH (2002). "Behavioral effects of delta-opioid receptor agonists: potential antidepressants?". Jpn. J. Pharmacol. 90 (1): 1–6.  
  8. ^ Torregrossa MM, Jutkiewicz EM, Mosberg HI, Balboni G, Watson SJ, Woods JH (2006). "Peptidic delta opioid receptor agonists produce antidepressant-like effects in the forced swim test and regulate BDNF mRNA expression in rats". Brain Res. 1069 (1): 172–81.  
  9. ^ Zhang H, Torregrossa MM, Jutkiewicz EM, Shi YG, Rice KC, Woods JH, Watson SJ, Ko MC (2006). "Endogenous opioids upregulate brain-derived neurotrophic factor mRNA through delta- and micro-opioid receptors independent of antidepressant-like effects". Eur. J. Neurosci. 23 (4): 984–94.  
  10. ^ Jutkiewicz EM, Torregrossa MM, Sobczyk-Kojiro K, Mosberg HI, Folk JE, Rice KC, Watson SJ, Woods JH (2006). "Behavioral and neurobiological effects of the enkephalinase inhibitor RB101 relative to its antidepressant effects". Eur. J. Pharmacol. 531 (1-3): 151–9.  
  11. ^ Zhang J, Qian H, Zhao P, Hong SS, Xia Y (2006). "Rapid hypoxia preconditioning protects cortical neurons from glutamate toxicity through delta-opioid receptor". Stroke 37 (4): 1094–9.  
  12. ^ Guo L, Zhang L, Zhang DC (2005). "[Mechanisms of delta-opioids cardioprotective effects in ischemia and its potential clinical applications]". Sheng li ke xue jin zhan [Progress in physiology] (in Chinese) 36 (4): 333–6.  
  13. ^ Calderon SN, Rothman RB, Porreca F, Flippen-Anderson JL, McNutt RW, Xu H, Smith LE, Bilsky EJ, Davis P, Rice KC (1994). "Probes for narcotic receptor mediated phenomena. 19. Synthesis of (+)-4-[(alpha R)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3- methoxybenzyl]-N,N-diethylbenzamide (SNC 80): a highly selective, nonpeptide delta opioid receptor agonist". J. Med. Chem. 37 (14): 2125–8.  
  14. ^ Calderon SN, Rice KC, Rothman RB, Porreca F, Flippen-Anderson JL, Kayakiri H, Xu H, Becketts K, Smith LE, Bilsky EJ, Davis P, Horvath R (1997). "Probes for narcotic receptor mediated phenomena. 23. Synthesis, opioid receptor binding, and bioassay of the highly selective delta agonist (+)-4-[(alpha R)-alpha-((2S,5R)-4-Allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]- N,N-diethylbenzamide (SNC 80) and related novel nonpeptide delta opioid receptor ligands". J. Med. Chem. 40 (5): 695–704.  
  15. ^ Jutkiewicz EM (2006). "The antidepressant -like effects of delta-opioid receptor agonists". Mol. Interv. 6 (3): 162–9.  
  16. ^ Ananthan S (2006). "Opioid ligands with mixed mu/delta opioid receptor interactions: an emerging approach to novel analgesics". AAPS J 8 (1): E118–25.  
  17. ^ Portoghese PS, Sultana M, Takemori AE (1988). "Naltrindole, a highly selective and potent non-peptide delta opioid receptor antagonist". Eur. J. Pharmacol. 146 (1): 185–6.  
  18. ^ Le Bourdonnec B, Windh RT, Ajello CW, Leister LK, Gu M, Chu GH, Tuthill PA, Barker WM, Koblish M, Wiant DD, Graczyk TM, Belanger S, Cassel JA, Feschenko MS, Brogdon BL, Smith SA, Christ DD, Derelanko MJ, Kutz S, Little PJ, DeHaven RN, DeHaven-Hudkins DL, Dolle RE (October 2008). "Potent, orally bioavailable delta opioid receptor agonists for the treatment of pain: discovery of N,N-diethyl-4-(5-hydroxyspiro[chromene-2,4'-piperidine]-4-yl)benzamide (ADL5859)". Journal of Medicinal Chemistry 51 (19): 5893–6.  
  19. ^ a b Kathmann M, Flau K, Redmer A, Tränkle C, Schlicker E (February 2006). "Cannabidiol is an allosteric modulator at mu- and delta-opioid receptors". Naunyn Schmiedebergs Arch. Pharmacol. 372 (5): 354–61.  
  20. ^ McVey M, Ramsay D, Kellett E, Rees S, Wilson S, Pope AJ, Milligan G (Apr 2001). "Monitoring receptor oligomerization using time-resolved fluorescence resonance energy transfer and bioluminescence resonance energy transfer. The human delta -opioid receptor displays constitutive oligomerization at the cell surface, which is not regulated by receptor occupancy". J. Biol. Chem. 276 (17): 14092–9.  
  21. ^ Cen B, Yu Q, Guo J, Wu Y, Ling K, Cheng Z, Ma L, Pei G (Mar 2001). "Direct binding of beta-arrestins to two distinct intracellular domains of the delta opioid receptor". J. Neurochem. 76 (6): 1887–94.  
  22. ^ Whistler JL, Enquist J, Marley A, Fong J, Gladher F, Tsuruda P, Murray SR, Von Zastrow M (Jul 2002). "Modulation of postendocytic sorting of G protein-coupled receptors".  

Further reading

External links