[D-Ala2]-Deltorphin II

[D-Ala2]-deltorphin II (DADELT II) is a natural agonist of δ opioid receptor with Ki or IC50 value of 0.41 nM [1, 2].

Opioid receptors are most abundant in the central nervous system, but are also localized in many peripheral tissues in mammalian organisms. there are three types of opioid receptors that are well-defined; the µ, δ and κ receptors [2].

[D-Pen2, D-Pen5]enkephalin (DPDPE) is a second highly selective agonist of δ [3]. Treatment with DPDPE at 1 M for as short as 3 min significantly diminished the inhibition of the opioid receptor in NG108-15 cells to cyclic AMP production. That means neuronal delta opioid receptor underwent acute desensitization. This desensitization was temporally parallel to the phosphorylation of delta opioid receptor 3 min. after agonist stimulation [4].

I.c.v. administration of DADELT II from 0.38-12.78 nM resulted in a dose- and time-related antinociception. 10 min after the administration of DADELT II, the maximal antinociceptive response was seen. Until 60 min after the administration of DADELT II, effects were detected. These antinociceptive effects of i.c.v. DADELT II were antagonized by the selective δ antagonist, ICI 174,864 [3]. After supraspinal and spinal administration in rats intracerebroventricularly, DADELT II at 0.2, 1, 10 μg/rat in a dose-related fashion inhibited diarrhea and colonic bead expulsion but did not show any effect on the rate of small intestine transit. Spinal administration of DADELT II at the same dose produced similar results. Naltrindole is a selective antagonist of the δ opioid receptor. Subcutaneous pretreatment with naltrindole at 1 and 10 mg/kg antagonized effects of DADELT II partially and completely, respectively [1].

References:
[1].  Broccardo M, Improta G. Antidiarrheal and colonic antipropulsive effects of spinal and supraspinal administration of the natural δ opioid receptor agonist,[D-Ala2] deltorphin II, in the rat. European journal of pharmacology, 1992, 218(1): 69-73.
[2].  Janecka A, Fichna J, Janecki T. Opioid receptors and their ligands. Current topics in medicinal chemistry, 2004, 4(1): 1-17.
[3].  Jiang Q, Mosberg HI, Porreca F. Antinociceptive effects of [D-Ala2] deltorphin II, a highly selective δ agonist in vivo. Life sciences, 1990, 47(11): PL43-PL47.
[4].  Cai Y, Zhang Y, Wu Y, et al. δ opioid receptor in neuronal cells undergoes acute and homologous desensitization. Biochemical and biophysical research communications, 1996, 219(2): 342-347.

Up-regulation of brain N-methyl-D-aspartate receptors following multiple intracerebroventricular injections of [D-Pen2, D-Pen5] enkephalin and [D-Ala2, Glu4]deltorphin II in mice.[Pubmed:9437723]

Peptides. 1997;18(10):1609-13.

The effects of chronic administration of [D-Pen2, D-Pen5]enkephalin and [D-Ala2, Glu4]deltorphin II, the selective agonists of the delta 1- and delta 2-opioid receptors, on the binding of [3H]MK-801, a noncompetitive antagonist of the N-methyl-D-aspartate receptor, were determined in several brain regions of the mouse. Male Swiss-Webster mice were injected intracerebroventricularly (i.c.v.) with [D-Pen2, D-Pen5]enkephalin or [D-Ala2, Glu4]deltorphin II (20 micrograms/mouse) twice a day for 4 days. Vehicle injected mice served as controls. Previously we have shown that the above treatment results in the development of tolerance to their analgesic activity. The binding of [3H]MK-801 was determined in brain regions (cortex, midbrain, pons and medulla, hippocampus, striatum, hypothalamus and amygdala). At 5 nM-concentration, the binding of [3H]MK-801 was increased in cerebral cortex, hippocampus, and pons and medulla of [D-Pen2, D-Pen5]enkephalin treated mice. In [D-Ala2, Glu4]deltorphin II treated mice, the binding of [3H]MK-801 was increased in cerebral cortex and hippocampus. The changes in the binding were due to increases in the Bmax value of [3H]MK-801. It is concluded that tolerance to delta 1- and delta 2-opioid receptor agonists is associated with up-regulation of brain N-methyl-D-aspartate receptors, however, some brain areas affected differ with the two treatments. The results are consistent with the recent observation from this laboratory that N-methyl-D-aspartate receptors antagonists block tolerance to the analgesic action of delta 1- and delta 2-opioid receptor agonists.

Effects of some 7-arylidene and 7-heteroarylidene morphinan-6-ones on the antinociceptive activity of [D-Pen2, D-Pen5]enkephalin and [D-Ala2, Glu4]deltorphin II and on multiple opioid receptors.[Pubmed:9213363]

Peptides. 1997;18(5):695-701.

The in vivo and functional effects of several 7-arylidene and 7-heteroarylidene morphinan-6-ones were determined at the mu-, delta-, and kappa-opioid receptors using the guinea pig brain membranes, guinea pig ileum (GPI), and mouse vas deferens (MVD). In vivo effects included the antagonism by these compounds given subcutaneously on the antinociceptive actions of intracerebroventricularly injected [D-Pen2, D-Pen5]enkephalin (DPDPE) and [D-Ala2, Glu4]deltorphin II (deltorphin II), the highly selective putative delta 1- and delta 2-opioid receptor agonists. Finally, the partition coefficients of these compounds were estimated (CLOGP) and determined experimentally at pH 7.4 in the 1-octanol/water system. Compared with E-7-benzylidenenaltrexone (BNTX), most compounds except for E-7-(4-chlorobenzylidene)naltrexone, were more potent at delta-opioid receptors than at the mu-opioid receptor, whereas, in comparison to the kappa-opioid receptor, the activities of the E-7-arylidene or E-7-heteroarylidene naltrexone derivatives at the delta-receptor were in the following order, where the 7-substituents were: 4-fluorobenzylidene- > benzylidene > 3-pyridylmethylene- > 4-pyridylmethylene- > 1-methyl-2-imidazolylmethylene > 4-chlorobenzylidene. In the MVD preparation, the potencies at the delta-opioid receptor, in comparison to BNTX, were in the following order, where the 7-substituents were: benzylidene = 1-methyl-2-imidazolylmethylene- > 4-fluorobenzylidene- = 3-pyridylmethylene- = 4-pyridylmethylene-. All compounds antagonized delta 1, and delta 2-opioid receptor agonist-induced analgesia. The antagonist potencies at the delta 1-opioid receptor were in the following order, where the 7-substituents were: benzylidene- > 4-chlorobenzylidene- > 4-fluorobenzylidene- > 3-pyridylmethylene- > 1-methyl-2-imidazolymethylene- approximately 4-pyridylmethylene-, whereas at the delta 2-opioid receptor, the order was benzylidene- > 4-chlorobenzylidene- > 4-fluorobenzylidene- > 3-pyridylmethylene- > 1-methyl-2-imidazolymethylene- > 4-pyridylmethylene. In general, all compounds exhibited greater potency at the delta 2- than delta 1-opioid receptor. The computed partition coefficients were, as expected, greater than the apparent log P values, which were determined experimentally. Generally, the lipophilicity values in decreasing order were: 4-chlorobenzylidene- > 4-fluorobenzylidene- > benzylidene > 3-pyridylmethylene- = 4-pyridylmethylene- > 1-methyl-2-imidazolylmethylene-. In general, the benzylidene and 4-pyridylmethylene derivatives, which have medium lipophilicities, were equally effective at the delta 1- and delta 2-receptors; the 3-pyridylmethylene and 1-methyl-2-imidazolylmethylene derivatives had lower lipophilicities and were more selective for the delta 2- than delta 1-receptor; the 4-chlorobenzylidene and 4-fluorobenzylidene derivatives were more lipophilic and had intermediate activity. The plot of pED50 values for the in vivo tests for the delta 1- and delta 2-receptors showed that the two receptors are not independent with respect to this series of compounds.

Structure-activity relationships of a series of [D-Ala2]deltorphin I and II analogues; in vitro blood-brain barrier permeability and stability.[Pubmed:9152390]

J Pharmacol Exp Ther. 1997 May;281(2):817-25.

[D-Ala2]deltorphins are enzymatically stable, amphibian heptapeptides that have a higher affinity and selectivity for delta-opioid receptors than any endogenous mammalian compound known. This study investigated the in vitro blood-brain barrier permeability, using primary bovine brain microvessel endothelium culture, and the resistance to enzymatic degradation, in mouse 15% brain membrane homogenates and 100% plasma, of [D-Ala2]deltorphin I, [D-Ala2]deltorphin II and several analogues. Derivatives were designed with the addition of N-terminal neutral and basic amino acids or with alterations of the amino acids present within the deltorphin sequences. The results indicated that the N-terminal sequence and the amino acids in position 4 and 5 are critical to deltorphin analogue BBB permeability and biological stability, i.e., t 1/2 brain; 4.8 hr- [D-Ala2]deltorphin I; > 15 hr- [D-Ala2, Ser4, D-Ala5]deltorphin. Although, no analogue was found to increase the BBB permeability coefficient (PC; x10(-4) cm/min) of the parent compounds ([D-Ala2]deltorphin II, PC = 23.49 +/- 2.42) analogues were identified: [Arg0, D-Ala2]deltorphin II, PC = 19.06 +/- 3.73 and [Pro-1, Pro0, D-Ala2]deltorphin II, PC = 22.22 +/- 5.93; which had similar permeability coefficients, even though they had larger molecular weights and, in the case of the cationic prodrug, a significantly lower lipophilicity. These analogues provide directions in the development of future pro-drugs for the treatment of pain and this study further clarifies the structure-activity relationship of the deltorphins.

Effects of multiple intracerebroventricular injections of [D-Pen2,D-Pen5]enkephalin and [D-Ala2,Glu4]deltorphin II on tolerance to their analgesic action and on brain delta-opioid receptors.[Pubmed:9037415]

Brain Res. 1997 Jan 16;745(1-2):243-7.

Male Swiss-Webster mice were injected intracerebroventricularly (i.c.v.) with [D-Pen2,D-Pen5]enkephalin (DPDPE), a delta 1-opioid receptor agonist (20 micrograms per mouse) twice a day for either 2 or 4 days. Vehicle injected mice served as controls. Treatment of mice with DPDPE for 2 or 4 days decreased its analgesic response by 44 and 76%, respectively in comparison to vehicle injected mice. Treatment of mice with DPDPE for 2 or 4 days decreased density (Bmax) of [3H]DPDPE to bind to brain homogenates by 77 and 76%, respectively, in comparison to vehicle injected controls but the apparent dissociation constant (kd) values were not altered. The effects of i.c.v. injections of [D-Ala2,Glu4]deltorphin II (deltorphin II), a delta 2-opioid receptor agonist (20 micrograms per mouse) twice a day for either 2 or 4 days on its analgesic response as well as on brain receptors for [3H]DPDPE were also determined. The analgesic response to deltorphin II decreased by 51 and 78%, respectively in mice treated with deltorphin II for 2 or 4 days, respectively. Two or four days treatment with deltorphin II decreased the Bmax of [3H]DPDPE by 76 and 87%, respectively. The 2-day treatment also increased the Kd value by 58%, but the 4-day treatment with deltorphin II had no effect on the Kd of [3H]DPDPE to bind to brain membranes. Thus, multiple injections of delta 1- or delta 2-opioid receptor agonists results in the development of tolerance to their analgesic action and the intensity of tolerance increases with the duration of treatment. Both delta 1- and delta 2-opioid receptor agonist, on chronic administration, result in the down-regulation of delta 1-opioid receptors labeled with [3H]DPDPE.

delta Opioid receptor subtypes activate inositol-signaling pathways in the production of antinociception.[Pubmed:9580632]

J Pharmacol Exp Ther. 1998 May;285(2):820-7.

To analyze the selectivity of delta receptor subtypes to regulate different classes of G proteins, the expression of the alpha-subunits of Gi2, Gi3, Go1, Go2, Gq and G11 transducer proteins was reduced by administration of oligodeoxynucleotides (ODNs) complementary to sequences in their respective mRNAs. Mice receiving antisense ODNs to Gi2 alpha, Gi3 alpha, Go2 alpha and G11 alpha subunits showed an impaired antinociceptive response to all the delta agonists evaluated. An ODN to Go1 alpha specifically blocked the antinociceptive effect of the agonist of delta-1 receptors, [D-Pen2,5]enkephalin (DPDPE), without altering the activity of [D-Ala2]deltorphin II or [D-Ser2]-Leu-enkephalin-Thr (DSLET). In mice treated with an ODN to Gq alpha, the effects of the agonists of delta-2-opioid receptors were reduced, but not those of DPDPE. Thus, Go1 proteins are selectively linked to delta-1-mediated analgesia, and Gq proteins are related to delta-2-evoked antinociception. After impairing the synthesis of Go1 alpha subunits, DPDPE exhibited an antagonistic activity on the antinociception produced by [D-Ala2]deltorphin II. After treatment with ODNs complementary to sequences in Gq alpha or PLC-beta 1 mRNAs, the analgesic capacity of [D-Ala2]deltorphin II was diminished. However, the delta-2-agonist did not alter the antinociceptive activity of DPDPE. An ODN complementary to nucleotides 7 to 26 of the murine delta receptor reduced the analgesic potency of [D-Ala2]deltorphin II, but not that observed for DPDPE. In these mice, [D-Ala2]deltorphin II did not antagonize the effect of DPDPE. These results suggest the existence of different molecular forms of the delta opioid receptor, and the involvement of inositol-signaling pathways in the supraspinal antinociceptive effects of delta agonists.

Lack of antinociceptive cross-tolerance between [D-Pen2, D-Pen5]enkephalin and [D-Ala2]deltorphin II in mice: evidence for delta receptor subtypes.[Pubmed:1650835]

J Pharmacol Exp Ther. 1991 Aug;258(2):583-7.

This study has investigated the development of antinociceptive tolerance to, and cross-tolerance between, two highly selective delta agonists, [D-Pen2,D-Pen5]enkephalin (DPDPE) and [D-Ala2] deltorphin II as well as to [D-Ala2,NMePhe4,Gly-ol5]enkephalin (DAMGO), a highly selective mu agonist, in mice. Intracerebroventricular administration of DPDPE, [D-Ala2]deltorphin II and DAMGO each produced an antinociceptive effect. Pretreatment with i.c.v. DPDPE twice daily for 3 days resulted in tolerance to DPDPE as shown by a 4.8-fold rightward shift in the dose-response curve. In contrast, in DPDPE pretreated mice, the dose-response lines for [D-Ala2]deltorphin II and DAMGO were not altered when compared to those obtained in naive animals. The development of tolerance was also shown by pretreating mice with i.c.v. [D-Ala2]deltorphin II; following this pretreatment, the [D-Ala2]deltorphin II dose-response line was displaced to the right by more than 37-fold. In contrast, in [D-Ala2]deltorphin II-pretreated mice, the dose-response lines for DPDPE and DAMGO were not altered compared to those obtained in naive animals. Finally, pretreatment with i.c.v. DAMGO produced a rightward displacement of the DAMGO dose-response line of 47-fold, indicating the development of antinociceptive tolerance. In DAMGO-pretreated mice, however, the dose-response lines for DPDPE and [D-Ala2]deltorphin II were not altered compared to those obtained in naive mice. Thus, the data indicate that antinociceptive tolerance develops to DPDPE, [D-Ala2]deltorphin II and DAMGO but that there is no cross-tolerance between these compounds.(ABSTRACT TRUNCATED AT 250 WORDS)