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Chemical Compound Review

DPDPE     (4R,7S,13R)-13-[[(2S)-2- amino-3-(4...

Synonyms: DPLPE, Dpdpe(SH)2, CHEBI:73356, KST-1A9063, Bis-pen-enkephalin, ...
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Disease relevance of Bis-pen-enkephalin

  • We demonstrate that the mechanical hyperalgesia induced by intradermal injection of BK can be blocked by the kappa-opioid agonist trans-3,4-dichloro-N-methyl-N[2-(-pyrrolidinyl)cyclo-hexyl] benzeneacetamide (U50,488H) and by the delta-opioid agonist (D-Pen2,5)-enkephalin (DPDPE), as well as the mu-opioid agonist Tyr-D-Ala-Gly-NMe-Phe-Gly-ol(DAMGO) [1].
  • DPDPE also induces adhesion of pertussis toxin-treated cells, indicating involvement of G proteins other than Gi [2].
  • 4. The addition of [Leu5]enkephalin, [Met5]enkephalin, PL017 (a mu-receptor agonist) and DPDPE (a delta-receptor agonist) to the ganglion side of a two-compartment chamber blocked distension-induced release of SP-LI material [3].
  • DAMGO and DPDPE also induced dose-dependent acidosis, with DAMGO again being much more potent than DPDPE [4].
  • Modulation of protein kinase C (PKC) and cAMP-dependent protein kinase (PKA) activities by delta-opioid receptor specific agonist [D-Pen2, D-Pen5]-enkephalin (DPDPE) was investigated in neuroblastoma x glioma hybrid NG 108-15 cells [5].

Psychiatry related information on Bis-pen-enkephalin

  • The effects of intracerebroventricular injection of the delta-selective opioid peptides, DADL (D-Ala2-D-Leu5-enkephalin) and DPLPE (D-Pen2-L-Pen5-enkephalin), on spontaneous locomotor activity were investigated in mice using multi-dimensional behavioral analysis, based upon a capacitance system [6].
  • Intrathecal administration of DPDPE, PL017, DAMGO, morphine and DADLE produced a dose-dependent increase in hot plate response latency, with the order of potency (ED50 nmol) being: DAMGO (0.17) > DADLE (0.70) > or = PL017 (1.2) > morphine (15) > DPDPE (130) [7].
  • The role of the ventral pallidum and the dorsal striatum in mediating the rewarding effects of the delta receptor specific agonist [2-D-penicillamine, 5-D-penicillamine]enkephalin (DPDPE) were evaluated in the rat using the intracranial self-stimulation paradigm [8].
  • The delta-opioid receptor was also involved in memory formation at this time-point since antagonism of this receptor by 1 mM ICI-174,864 caused amnesia (P<0.01) which was reversed by the agonist, DPLPE [9].
  • The delta-opioid receptor antagonist naltrindole (1-5 mg/kg i.p. 15 min before the session) had no effect on alcohol drinking, while it attenuated the delta-opioid receptor agonist [D-Pen2, D-Pen5]enkephalin-induced locomotor stimulation [10].

High impact information on Bis-pen-enkephalin

  • Fifty percent (22 of 45) of pyramidal cells were hyperpolarized by [Met5]enkephalin; this resulted from an increase in potassium conductance, and it was mimicked by DPDPE and blocked by naltrindole [11].
  • By binding to its specific receptor, the opioid receptor-specific ligand DPDPE triggers monocyte adhesion [2].
  • Src inhibitor PP2 also prolonged ERK stimulation by DPDPE [12].
  • Our result showed that removing the C terminus of delta opioid receptor (DOR) containing six Ser/Thr residues abolished both DPDPE- and phorbol 12-myristate 13-acetate (PMA)-induced DOR phosphorylation [13].
  • We found that only two residues, i.e. Thr(358) and Ser(363), were phosphorylated, with Ser(363) being critical for the DPDPE-induced phosphorylation of the receptor [14].

Chemical compound and disease context of Bis-pen-enkephalin

  • The elevations of [Ca2+]i by DPDPE and DAMGO were abolished by pretreatment of the cells with pertussis toxin (200 ng ml-1, 16 h) [15].
  • The present study compared morphine pellets to morphine pumps and also examined the differential effects of morphine versus U50,488H (kappa agonist), deltorphin II (delta2 agonist), and (D-Pen2, D-Pen5)-enkephalin (DPDPE, delta1 agonist), administered via Alzet minipumps, on oral Salmonella infection and on gastrointestinal transit [16].
  • In contrast, DPDPE and U50-488H increased lordosis quotients and magnitudes significantly in both steroid-treatment groups [17].
  • These possible solution conformers of DPDPE in both DMSO and water share virtually the same type of cyclic backbone structure, with the Gly3 residue in a conformation close to a gamma-turn, and the Phe4 residue in a conformation close to alpha-helical torsion angles [18].

Biological context of Bis-pen-enkephalin

  • Inhibition of endocytosis by sucrose prolonged ERK activation by DPDPE increasing the decay half-life of the response to values that resembled those of dual efficacy ligands (from a 2-min decay t((1/2)) increased to 12 min) [12].
  • In these experiments fluo-3/AM incubated cells showed a rapidly induced delta-opioid agonist (DPDPE, 10(-6) M) evoked increase in [Ca2+]i. These results suggest an upregulation of the delta-opioid receptors that could represent a mechanism involved in the response to opioids in the developing brain [19].
  • The DPDPE-imprinted polymer showed a broad structure-activity relationship profile, not unlike that found for protein receptors [20].
  • Here we report, for the first time, the formation of a biomimetic covalently imprinted polymeric sensor for a target ligand, the delta-opioid G-protein coupled receptor agonist DPDPE, which reproducibly exhibits subpicomolar binding affinity in an aqueous environment [20].
  • Binding sites for [3H]-[D-Pen2, D-Pen5]enkephalin (DPDPE) could not be detected [21].

Anatomical context of Bis-pen-enkephalin

  • In addition to a selectivity similar to that of the cyclic compounds [D-Pen2, D-Pen5]enkephalin and [D-Pen2,L-Pen5]enkephalin, the affinity of [3H][D-Ser2(O-tert-butyl),Leu5]enkephalyl-Thr6 for the delta sites of rat brain membranes is significantly better (KD = 2.2 nM) than that of [3H][D-Pen2,D-Pen5]enkephalin (KD approximately 8.5 nM) [22].
  • However, in the same cell lines under the same conditions, overexpression of beta-adrenergic receptor kinase 2 and beta-arrestin 2 accelerated the rate of DPDPE- but not DAMGO-induced receptor desensitization [23].
  • The contribution of individual opioid receptor subtypes in the spinal cord to analgesia were tested at different developmental stages using epidural mu (morphine sulphate), delta (DPDPE) and kappa (U69593) opioid receptor agonists in neonatal rats aged P (postnatal day) 3, 10 and 21 [24].
  • However, because only modest analgesic effects were seen after subcutaneous administration of DPDPE, it has been inferred that it does not cross the blood-brain barrier well [25].
  • DPDPE proved highly potent in competing with its tritiated analogue at delta-receptors of NG108-15 hybrid cells and of High 5 and Sf9 insect cells [26].

Associations of Bis-pen-enkephalin with other chemical compounds


Gene context of Bis-pen-enkephalin

  • RGS7-deficient mice showed an increased response to both [D-Ala(2)]deltorphin II and DPDPE analgesic effects [29].
  • Our results show that superantigen-induced clonal deletion is promoted by DPDPE and significantly impaired in DOR-1-deficient mice [30].
  • These results demonstrate that OATP-A can mediate transport of the analgesic opioid peptides DPDPE and deltorphin II across the human BBB [31].
  • When NPY (30 nM) or SRIF (100 nM) was applied together with a maximally effective concentration of the delta-opioid receptor agonist DPDPE ([D-Pen2,5]-enkephalin) (1 microM), the resulting elevations of [Ca2+]i were not greater than those caused by application of DPDPE alone [32].
  • Following treatment with any of the three opioid agonists (mu, DAMGO; delta, DPDPE; kappa, U50488H), the number of CGRP- and SP-IR cultured DRG neurons increased significantly, and in a concentration-dependent manner, with the effects of kappa agonist being less pronounced [33].

Analytical, diagnostic and therapeutic context of Bis-pen-enkephalin

  • The direct phosphorylation of phospholipase C was demonstrated by immunoprecipitation of PLC-beta3 from metabolically labeled NG108-15 cells challenged with the delta-selective agonist [D-Pen2, D-Pen5]enkephalin (DPDPE) [27].
  • [D-Penicillamine2,5] enkephalin (DPDPE) is an enzymatically stable, delta-opioid receptor-selective peptide, which produces analgesia when given intracerebroventricularly [25].
  • The eight analogues of DPDPE showed highly variable binding and bioassay activities particularly at the delta opioid receptor (4 orders of magnitude), but also at the mu opioid receptor, which led to large differences (3 orders of magnitude) in receptor selectivity [34].
  • Furthermore, HPLC analysis confirmed the integrity of the 3H to DPDPE and demonstrated that intact [3H]DPDPE entered the brain [25].
  • The increase in tail-flick latency produced by microinjection of DPDPE into the NRM or NGCpalpha was antagonized by intrathecal pretreatment with either methysergide or yohimbine [35].


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  5. Modulation of protein kinase C and cAMP-dependent protein kinase by delta-opioid. Lou, L.G., Pei, G. Biochem. Biophys. Res. Commun. (1997) [Pubmed]
  6. Multi-dimensional analysis of behavior in mice treated with the delta opioid agonists DADL (D-Ala2-D-Leu5-enkephalin) and DPLPE (D-Pen2-L-Pen5-enkephalin). Ukai, M., Toyoshi, T., Kameyama, T. Neuropharmacology (1989) [Pubmed]
  7. Isobolographic and dose-response analyses of the interaction between intrathecal mu and delta agonists: effects of naltrindole and its benzofuran analog (NTB). Malmberg, A.B., Yaksh, T.L. J. Pharmacol. Exp. Ther. (1992) [Pubmed]
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  13. Heterologous activation of protein kinase C stimulates phosphorylation of delta-opioid receptor at serine 344, resulting in beta-arrestin- and clathrin-mediated receptor internalization. Xiang, B., Yu, G.H., Guo, J., Chen, L., Hu, W., Pei, G., Ma, L. J. Biol. Chem. (2001) [Pubmed]
  14. Hierarchical phosphorylation of delta-opioid receptor regulates agonist-induced receptor desensitization and internalization. Kouhen, O.M., Wang, G., Solberg, J., Erickson, L.J., Law, P.Y., Loh, H.H. J. Biol. Chem. (2000) [Pubmed]
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  16. Effects of mu, kappa or delta opioids administered by pellet or pump on oral Salmonella infection and gastrointestinal transit. Feng, P., Rahim, R.T., Cowan, A., Liu-Chen, L.Y., Peng, X., Gaughan, J., Meissler, J.J., Adler, M.W., Eisenstein, T.K. Eur. J. Pharmacol. (2006) [Pubmed]
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  18. Solution conformations of the peptide backbone for DPDPE and its beta-MePhe4-substituted analogs. Nikiforovich, G.V., Prakash, O.M., Gehrig, C.A., Hruby, V.J. Int. J. Pept. Protein Res. (1993) [Pubmed]
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  22. [3H][D-Ser2(O-tert-butyl),Leu5]enkephalyl-Thr6 and [D-Ser2(O-tert-butyl),Leu5]enkephalyl-Thr6(O-tert-butyl). Two new enkephalin analogs with both a good selectivity and a high affinity toward delta-opioid binding sites. Delay-Goyet, P., Seguin, C., Gacel, G., Roques, B.P. J. Biol. Chem. (1988) [Pubmed]
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  28. The RGSZ2 protein exists in a complex with mu-opioid receptors and regulates the desensitizing capacity of Gz proteins. Garzón, J., Rodríguez-Muñoz, M., López-Fando, A., Sánchez-Blázquez, P. Neuropsychopharmacology (2005) [Pubmed]
  29. The R7 subfamily of RGS proteins assists tachyphylaxis and acute tolerance at mu-opioid receptors. Garzón, J., López-Fando, A., Sánchez-Blázquez, P. Neuropsychopharmacology (2003) [Pubmed]
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  32. Neuropeptide Y Y2 receptor and somatostatin sst2 receptor coupling to mobilization of intracellular calcium in SH-SY5Y human neuroblastoma cells. Connor, M., Yeo, A., Henderson, G. Br. J. Pharmacol. (1997) [Pubmed]
  33. Expression of calcitonin gene-related peptide, substance P and protein kinase C in cultured dorsal root ganglion neurons following chronic exposure to mu, delta and kappa opiates. Belanger, S., Ma, W., Chabot, J.G., Quirion, R. Neuroscience (2002) [Pubmed]
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