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1.  Effect of δ-Opioid Receptor Activation on BDNF-TrkB vs. TNF-α in the Mouse Cortex Exposed to Prolonged Hypoxia 
We investigated whether δ-opioid receptor (DOR)-induced neuroprotection involves the brain-derived neurotrophic factor (BDNF) pathway. We studied the effect of DOR activation on the expression of BDNF and other proteins in the cortex of C57BL/6 mice exposed to hypoxia (10% of oxygen) for 1–10 days. The results showed that: (1) 1-day hypoxia had no appreciable effect on BDNF expression, while 3- and 10-day hypoxia progressively decreased BDNF expression, resulting in 37.3% reduction (p < 0.05) after 10-day exposure; (2) DOR activation with UFP-512 (1 mg/kg, i.p., daily) partially reversed the hypoxia-induced reduction of BDNF expression in the 3- or 10-day exposed cortex; (3) DOR activation partially reversed the hypoxia-induced reduction in functional TrkB (140-kDa) and attenuated hypoxia-induced increase in truncated TrkB (90-kDa) in the 3- or 10-day hypoxic cortex; and (4) prolonged hypoxia (10 days) significantly increased TNF-α level and decreased CD11b expression in the cortex, which was completely reversed following DOR activation; and (5) there was no significant change in pCREB and pATF-1 levels in the hypoxic cortex. We conclude that prolonged hypoxia down-regulates BDNF-TrkB signaling leading to an increase in TNF-α in the cortex, while DOR activation up-regulates BDNF-TrkB signaling thereby decreasing TNF-α levels in the hypoxic cortex.
doi:10.3390/ijms140815959
PMCID: PMC3759895  PMID: 23912236
δ-opioid receptor; brain-derived neurotrophic factor (BDNF); TNF-α; hypoxia; neuroprotection
2.  Hydrogen Sulfide Induced Disruption of Na+ Homeostasis in the Cortex 
Toxicological Sciences  2012;128(1):198-208.
Maintenance of ionic balance is essential for neuronal functioning. Hydrogen sulfide (H2S), a known toxic environmental gaseous pollutant, has been recently recognized as a gasotransmitter involved in numerous biological processes and is believed to play an important role in the neural activities under both physiological and pathological conditions. However, it is unclear if it plays any role in maintenance of ionic homeostasis in the brain under physiological/pathophysiological conditions. Here, we report by directly measuring Na+ activity using Na+ selective electrodes in mouse cortical slices that H2S donor sodium hydrosulfide (NaHS) increased Na+ influx in a concentration-dependent manner. This effect could be partially blocked by either Na+ channel blocker or N-methyl-D-aspartate receptor (NMDAR) blocker alone or almost completely abolished by coapplication of both blockers but not by non-NMDAR blocker. These data suggest that increased H2S in pathophysiological conditions, e.g., hypoxia/ischemia, potentially causes a disruption of ionic homeostasis by massive Na+ influx through Na+ channels and NMDARs, thus injuring neural functions. Activation of delta-opioid receptors (DOR), which reduces Na+ currents/influx in normoxia, had no effect on H2S-induced Na+ influx, suggesting that H2S-induced disruption of Na+ homeostasis is resistant to DOR regulation and may play a major role in neuronal injury in pathophysiological conditions, e.g., hypoxia/ischemia.
doi:10.1093/toxsci/kfs125
PMCID: PMC3391029  PMID: 22474073
hydrogen sulfide; Na+ homeostasis; ionotropic glutamate receptor; Na+ channel; delta-opioid receptor; cortex
3.  Prokineticin Receptor 1 Antagonist PC-10 as a Biomarker for Imaging Inflammatory Pain 
Prokineticin receptor 1 (PKR1) and its ligand Bv8 were shown to be expressed in inflammation-induced pain and by tumor-supporting fibroblasts. Blocking this receptor might prove useful for reducing pain and for cancer therapy. However, there is no method to quantify the levels of these receptors in vivo.
Methods
A nonpeptidic PKR1 antagonist, N-{2-[5-(4-fluoro-benzyl)-1-(4-methoxy-benzyl)-4,6-dioxo-1,4,5,6-tetrahydro-[1,3,5] triazin-2-ylamino]-ethyl}-guanidine, which contains a free guanidine group, was labeled with 18F by reacting the guanidine function with N-succinimidyl-4-18F-fluorobenzoate to give the guanidinyl amide N-(4-18F-fluoro-benzoyl)-N′-{2-[5-(4-fluoro-benzyl)-1-(4-methoxy-benzyl)-4,6-dioxo-1,4,5,6-tetrahydro-[1,3,5] triazin-2-ylamino]-ethyl}-guanidine (18F-PC-10). Inflammation was induced in C57BL/6 mice by subcutaneous injection of complete Freund adjuvant in the paw. The mice were imaged with 18F-PC-10, 18F-FDG, and 64Cu-pyruvaldehyde bis(4-methyl-3-thiosemicarbazone) (64Cu-PTSM) at 24 h after complete Freund adjuvant injection using a small-animal PET device.
Results
18F-PC-10 was synthesized with a radiochemical yield of 16% ± 3% (decay-corrected). 18F-PC-10 accumulated specifically in the inflamed paw 4- to 5-fold more than in the control paw. Compared with 18F-PC-10, 18F-FDG and 64Cu-PTSM displayed higher accumulation in the inflamed paw but also had higher accumulation in the control paw, demonstrating a reduced signal-to-background ratio. 18F-PC-10 also accumulated in PKR1-expressing organs, such as the salivary gland and gastrointestinal tract.
Conclusion
18F-PC-10 can be used to image PKR1, a biomarker of the inflammation process. However, the high uptake of 18F-PC-10 in the gastrointestinal tract, due to specific uptake and the metabolic processing of this highly lipophilic molecule, would restrict its utility.
doi:10.2967/jnumed.110.084772
PMCID: PMC3629974  PMID: 21421710
prokineticin receptor; inflammation; positron emission tomography (PET); 18F
4.  δ-Opioid Receptor Activation Modified MicroRNA Expression in the Rat Kidney under Prolonged Hypoxia 
PLoS ONE  2013;8(4):e61080.
Hypoxic/ischemic injury to kidney is a frequently encountered clinical problem with limited therapeutic options. Since microRNAs are differentially involved in hypoxic/ischemic events and δ-opioid receptor (DOR) activation is known to protect against hypoxic/ischemic injury, we speculated on the involvement of DOR activation in altering the microRNA (miRNA) expression in kidney under hypoxic condition. We selected 31 miRNAs based on microarray data for quantitative PCR analysis. Among them, 14 miRNAs were significantly altered after prolonged hypoxia, DOR activation or a combination of both. We found that 1) DOR activation alters miRNA expression profiles in normoxic conditions; 2) hypoxia differentially alters miRNA expression depending on the duration of hypoxia; and 3) DOR activation can modify hypoxia-induced changes in miRNA expression. For example, 10-day hypoxia reduced the level of miR-212 by over 70%, while DOR activation could mimic such reduction even in normoxic kidney. In contrast, the same stress increased miR-29a by >100%, which was reversed following DOR activation. These first data suggest that hypoxia comprehensively modifies the miRNA profile within the kidney, which can be mimicked or modified by DOR activation. Ascertaining the targeted pathways that regulate the diverse cellular and molecular functions of miRNA may provide new insights into potential therapies for hypoxic/ischemic injury of the kidney.
doi:10.1371/journal.pone.0061080
PMCID: PMC3626642  PMID: 23596515
5.  Synthesis and separation of the enantiomers of the Neuropeptide S receptor antagonist (9R/S)-3-Oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (SHA 68) 
Journal of medicinal chemistry  2011;54(8):2738-2744.
This study reports the synthesis, chromatographic separation and pharmacological evaluation of the two enantiors of the neuropeptide S receptor (NPSR) antagonist (9R/S)-3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (SHA 68). The (9R)-3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (compound 10) and (9S)-3-oxo-1,1-diphenyl-tetrahydro-oxazolo[3,4-a]pyrazine-7-carboxylic acid 4-fluoro-benzylamide (compound 10a) were synthesized and their purity assessed by chiral chromatography. The absolute configuration of the enantiomer 10 has been assigned from the crystal structure of the corresponding (S)-phenyl ethyl amine derivative 8. Calcium mobilization studies performed on cells expressing the recombinant NPSR demonstrated that compound 10 is the active enantiomer while the contribution of 10a to the NPSR antagonist properties of the racemic mixture is negligible.
doi:10.1021/jm200138r
PMCID: PMC3095364  PMID: 21466221
6.  Opioid Bifunctional Ligands from Morphine and the Opioid Pharmacophore Dmt-Tic 
Bifunctional ligands containing an ester linkage between morphine and the δ-selective pharmacophore Dmt-Tic were synthesized, and their binding affinity and functional bioactivity at the μ, δ and κ opioid receptors determined. Bifunctional ligands containing or not a spacer of β-alanine between the two pharmacophores lose the μ agonism deriving from morphine becoming partial μ agonists 4 or μ antagonists 5. Partial κ agonism is evidenced only for compound 4. Finally, both compounds showed potent δ antagonism.
doi:10.1016/j.ejmech.2010.12.001
PMCID: PMC3035428  PMID: 21216504
7.  Role of 2′,6′-Dimethyl-L-Tyrosine (Dmt) in Some Opioid Lead Compounds 
Bioorganic & medicinal chemistry  2010;18(16):6024-6030.
Here we evaluated how the interchange of the amino acids 2′,6′-dimethyl-L-tyrosine (Dmt), 2′,6′-difluoro-L-tyrosine (Dft), and tyrosine in position 1 can affect the pharmacological characterization of some reference opioid peptides and pseudopeptides. Generally, Dft and Tyr provide analogues with a similar pharmacological profile, despite different pKa values. Dmt/Tyr(Dft) replacement gives activity changes depending on the reference opioid in which the modification was made. Whereas, H-Dmt-Tic-Asp*-Bid is a potent and selective δ agonist (MVD, IC50 = 0.12 nM); H-Dft-Tic-Asp*-Bid and H-Tyr-Tic-Asp*-Bid are potent and selective δ antagonists (pA2 = 8.95 and 8.85, respectively). When these amino acids are employed in the synthesis of deltorphin B and its Dmt1 and Dft1 analogues, the three compounds maintain a very similar δ agonism (MVD, IC50 0.32–0.53 nM) with a decrease in selectivity relative to the Dmt1 analogue. In the less selective H-Dmt-Tic-Gly*-Bid the replacement of Dmt with Dft and Tyr retains the δ agonism but with a decrease in potency. Antagonists containing the Dmt-Tic pharmacophore do not support the exchange of Dmt with Dft or Tyr.
doi:10.1016/j.bmc.2010.06.073
PMCID: PMC2918654  PMID: 20637637
Dmt-Tic pharmacophore; opioid peptides; opioid receptors; δ opioid agonists; UFP-512; δ opioid antagonists
8.  Novel multiple opioid ligands based on 4-aminobenzazepinone (Aba), azepinoindole (Aia) and tetrahydroisoquinoline (Tic) scaffolds 
The dimerization and trimerization of the Dmt-Tic, Dmt-Aia and Dmt-Aba pharmacophores provided multiple ligands which were evaluated in vitro for opioid receptor binding and functional activity. Whereas the Tic- and Aba multimers proved to be dual and balanced δ/μ antagonists, as determined by the functional [S35]GTPγS binding assay, the dimerization of potent Aia-based ‘parent’ ligands unexpectedly resulted in substantial less efficient receptor binding and non-active dimeric compounds.
doi:10.1016/j.bmcl.2010.01.055
PMCID: PMC2840614  PMID: 20137938
9.  Evolution of the Bifunctional Lead μ Agonist / δ Antagonist Containing the Dmt-Tic Opioid Pharmacophore 
ACS chemical neuroscience  2010;1(2):155-164.
Based on a renewed importance recently attributed to bi- or multifunctional opioids, we report the synthesis and pharmacological evaluation of some analogues derived from our lead μ agonist / δ antagonist, H-Dmt-Tic-Gly-NH-Bzl. Our previous studies focused on the importance of the C-teminal benzyl function in the induction of such bifunctional activity. The introduction of some substituents in the para position of the phenyl ring (-Cl, -CH3, partially −NO2, inactive -NH2) was found to give a more potent μ agonist / antagonist effect associated with a relatively unmodified δ antagonist activity (pA2 = 8.28-9.02). Increasing the steric hindrance of the benzyl group (using diphenylmethyl and tetrahydroisoquinoline functionalities) substantially maintained the μ agonist and δ antagonist activities of the lead compound. Finally and quite unexpectedly D-Tic2, considered as a wrong opioid message now; inserted into the reference compound in lieu of L-Tic, provided a μ agonist / δ agonist better than our reference ligand (H-Dmt-Tic-Gly-NH-Ph) and was endowed with the same pharmacological profile.
doi:10.1021/cn900025j
PMCID: PMC2843921  PMID: 20352071
10.  Evolution of the Bifunctional Lead μ Agonist/δ Antagonist Containing the 2′,6′-Dimethyl-l-tyrosine−1,2,3,4-Tetrahydroisoquinoline-3-carboxylic Acid (Dmt−Tic) Opioid Pharmacophore 
ACS Chemical Neuroscience  2009;1(2):155-164.
Based on a renewed importance recently attributed to bi- or multifunctional opioids, we report the synthesis and pharmacological evaluation of some analogues derived from our lead μ agonist/δ antagonist, H-Dmt-Tic-Gly-NH-Bzl (Dmt = 2′,6′-dimethyl-l-tyrosine, Tic = 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, Bzl = benzyl). Our previous studies focused on the importance of the C-teminal benzyl function in the induction of such bifunctional activity. The introduction of some substituents in the para position of the phenyl ring (−Cl, −CH3, partially −NO2, inactive −NH2) was found to give a more potent μ agonist/antagonist effect associated with a relatively unmodified δ antagonist activity (pA2 = 8.28−9.02). Increasing the steric hindrance of the benzyl group (using diphenylmethyl and tetrahydroisoquinoline functionalities) substantially maintained the μ agonist and δ antagonist activities of the lead compound. Finally and quite unexpectedly d-Tic2, considered as a wrong opioid message now, inserted into the reference compound in lieu of l-Tic provided a μ agonist/δ agonist better than our reference ligand (H-Dmt-Tic-Gly-NH-Ph; Ph = phenyl) and was endowed with the same pharmacological profile.
doi:10.1021/cn900025j
PMCID: PMC2843921  PMID: 20352071
Bifunctional opioids; Dmt−Tic pharmacophore; opioid peptides; opioid receptors, angiogenesis, tolerance
11.  Prototypic Opioid Peptidomimetics Based on the Dmt-Aba-Gly Scaffold 
Journal of medicinal chemistry  2006;49(13):3990-3993.
Peptidomometic analogues, H-Dmt-Tic-NH2-CH2-Ph or -Bid exhibit δ-opioid receptor activities. Substitution of Tic by the Aba-Gly scaffold coupled to the C-termini -CH2-Ph (1), -NH-Ph (2) and Gly*-Bid (3) shifted receptor affinity and selectivity to μ-opioid receptors (Kiμ = 0.46, 1.48 and 19.9 nM, respectively) with μ agonism. These represent templates for a new class of μ-opioid agonists. Further modification with negative or positive charges could yield altered properties suitable for therapeutic application for pain relief.
doi:10.1021/jm0603264
PMCID: PMC2983084  PMID: 16789756
12.  Orally administered H-Dmt-Tic-Lys-NH-CH2-Ph (MZ-2), a potent μ-/δ-opioid receptor antagonist, regulates obese-related factors in mice 
European journal of pharmacology  2009;616(1-3):115-121.
Orally active dual μ-/δ-opioid receptor antagonist, H-Dmt-Tic-Lys-NH-CH2-Ph (MZ-2) was applied to study body weight gain, fat content, bone mineral density, serum insulin, cholesterol and glucose levels in female ob/ob (B6.V-Lep/J homozygous) and lean wild mice with or without voluntary exercise on wheels for three weeks, and during a two week post-treatment period under the same conditions. MZ-2 (10 mg/kg/day, p.o.) exhibited the following actions: (1) reduced body weight gain in sedentary obese mice that persisted beyond the treatment period without effect on lean mice; (2) stimulated voluntary running on exercise wheels of both groups of mice; (3) decreased fat content, enhanced bone mineral density (BMD), and decreased serum insulin and glucose levels in obese mice; and (4) MZ-2 (30 μM) increased BMD in human osteoblast cells (MG-63) comparable to naltrexone, while morphine inhibited mineral nodule formation. Thus, MZ-2 has potential application in the clinical management of obesity, insulin and glucose levels, and the amelioration of osteoporosis.
doi:10.1016/j.ejphar.2009.06.041
PMCID: PMC2750889  PMID: 19576206
obesity; ob/ob mice; bone mineral density; insulin; glucose; Dmt-Tic pharmacophore; dual μ-/δ-opioid receptor antagonist
13.  Further studies at neuropeptide S position 5: discovery of novel neuropeptide S receptor antagonists 
Journal of medicinal chemistry  2009;52(13):4068-4071.
Neuropeptide S (NPS) regulates various biological functions by activating the NPS receptor (NPSR). Previous studies demonstrated that the substitution of Gly5 with D-amino acids generates NPSR antagonists. Eleven [D-Xaa5]NPS derivatives were synthesized and pharmacologically tested measuring [Ca2+]i in HEK293mNPSR cells. The present results confirmed that the [D-Xaa5] substitution promotes antagonist activity with potency inversely related to the side chain size and allowed to identify the novel potent NPSR peptide antagonist [tBu-D-Gly5]NPS.
doi:10.1021/jm900604g
PMCID: PMC2732566  PMID: 19473027
14.  Na+ mechanism of δ-opioid receptor induced protection from anoxic K+ leakage in the cortex 
Activation of δ-opioid receptors (DOR) attenuates anoxic K+ leakage and protects cortical neurons from anoxic insults by inhibiting Na+ influx. It is unknown, however, which pathway(s) that mediates the Na+ influx is the target of DOR signal. In the present work, we found that in the cortex, 1) DOR protection was largely dependent on the inhibition of anoxic Na+ influxes mediated by voltage-gated Na+ channels; 2) DOR activation inhibited Na+ influx mediated by ionotropic glutamate NMDA receptors, but not that by non-NMDA receptors though both played a role in anoxic K+ derangement; and 3) DOR activation had little effect on Na+/Ca2+ exchanger-based response to anoxia. We conclude that, 1) DOR activation attenuates anoxic K+ derangement by restricting Na+ influx mediated by Na+ channels and NMDA receptors, and 2) non-NMDA receptors and Na+/Ca2+ exchangers, though involved in anoxic K+ derangement in certain degrees, are less likely the targets of DOR signal.
doi:10.1007/s00018-009-8759-5
PMCID: PMC2704459  PMID: 19189047
anoxia; cortex; δ-opioid receptor; K+ homeostasis; Na+ channels; ionotropic glutamate receptor channels
15.  In vitro and in vivo pharmacological characterization of the neuropeptide S receptor antagonist [D-Cys(tBu)5]NPS 
Neuropeptide S (NPS) was identified as the endogenous ligand of an orphan receptor now referred to as NPSR. In the frame of a structure-activity study performed on NPS Gly5, the NPSR ligand [D-Cys(tBu)5]NPS was identified. [D-Cys(tBu)5]NPS up to 100 μM did not stimulate calcium mobilization in HEK293 cells stably expressing the mouse NPSR (HEK293mNPSR), however, the peptide inhibited in a concentration dependent manner the stimulatory effects elicited by 10 and 100 nM NPS (pK 6.62). In Schild analysis experiments [D-Cys(tBu)5]NPS (0.1 - 100 μM) produced a concentration dependent and parallel rightward shift of the concentration response curve to NPS showing a pA2 value of 6.44. 10 μM [D-Cys(tBu)5]NPS did not affect signalling at seven NPSR unrelated G-protein coupled receptors. In the mouse righting reflex (RR) recovery test, NPS given at 0.1 nmole intracerebroventricularly reduced the percent of animals losing the RR in response to diazepam 15 mg/kg and their sleeping time. [D-Cys(tBu)5]NPS (1-10 nmoles) was inactive per se but dose dependently antagonized the arousal-promoting action of NPS. Finally, NPSR-deficient mice were similarly sensitive to the hypnotic effects of diazepam as their wild-type littermates. However, the arousal promoting action of 1 nmole NPS could be detected in wild-type but not in mutant mice. In conclusion, [D-Cys(tBu)5]NPS behaves both in vitro and in vivo as a pure and selective NPSR antagonist, but with moderate potency. Moreover, using this tool together with receptor knockout mice studies we demonstrated that the arousal-promoting action of NPS is due to the selective activation of the NPSR protein.
doi:10.1124/jpet.108.143867
PMCID: PMC2630366  PMID: 18971372
16.  Further Studies on Lead Compounds Containing the Opioid Pharmacophore Dmt-Tic 
Journal of medicinal chemistry  2008;51(16):5109-5117.
Opioids containing the Dmt-Tic pharmacophore, especially the δ agonists H-Dmt-Tic-Gly-NH-Ph 1 and H-Dmt-Tic-NH-(S)CH(CH2-COOH)-Bid 4 (UFP-512) were evaluated for the influence of the substitution of Gly with aspartic acid, its chirality, and the importance of the – NH-Ph and N1H-Bid hydrogens relative to δ agonism. The results provide the following conclusions: (i) Asp increases δ selectivity by lowering μ affinity; (ii) -NH-Ph and N1H-Bid nitrogen methylation transforms δ agonists into δ antagonists; (iii) substitution of Gly with L-Asp/D-Asp in the δ agonist H-Dmt-Tic-Gly-NH-Ph resulted in δ antagonists, while the same substitution in the δ agonist H-Dmt-Tic-NH-CH2-Bid yielded more selective δ agonists, H-Dmt-Tic-NH-(S)CH(CH2-COOH)-Bid and H-Dmt-Tic-NH-(R)CH(CH2-COOH)-Bid; (iv) L-Asp seems important only for functional bioactivity, not receptor affinity; (v) H-Dmt-Tic-NH-(S)CH(CH2-COOH)-Bid(N1-Me) (10) revealed analgesia similar to 4, which was reversed by naltrindole only in the tail-flick test. Compounds 4 and 10 had opposite behaviours in mice: 4 caused agitation, while 10 gave sedation and convulsions.
doi:10.1021/jm800587e
PMCID: PMC2812024  PMID: 18680274
17.  Synthesis and biological activity of human neuropeptide S analogues modified in position 5 
Journal of medicinal chemistry  2009;52(2):524-529.
Neuropeptide S (NPSa), the endogenous ligand of a previously orphan receptor now named NPSR, regulates various biological functions in the brain, including arousal, locomotion, anxiety, and food intake. Here we report on a focused structure-activity study of Gly5 which has been replaced with L and D amino acids. Fifteen NPS related peptides were synthesized and pharmacologically tested for intracellular calcium mobilization using HEK293 cells stably expressing the mouse NPSR. The results of this study demonstrated that peptide potency is inversely related to the side chain size while peptide efficacy strongly depends on the relative L and D configuration with the L aminoacids favoring agonist while D aminoacids displaying antagonist pharmacological activity. [D-Val5]NPS behaved as NPSR pure antagonist in HEK293mNPSR cells showing the highest potency (pKB 7.56) among this series of peptides. The antagonist action of [D-Val5]NPS was confirmed in vivo in mice where the peptide at a dose of 10 nmoles completely blocked the stimulatory effect of 0.1 nmole NPS on locomotor activity.
doi:10.1021/jm8012294
PMCID: PMC2653091  PMID: 19113861
18.  Conformationally constrained opioid ligands: The Dmt-Aba and Dmt-Aia vs. Dmt-Tic scaffold 
Replacement of the constrained phenylalanine analogue 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic) in the opioid Dmt-Tic-Gly-NH-Bn scaffold by the 4-amino-1,2,4,5-tetrahydro-indolo[2,3-c]azepin-3-one (Aia) and 4-amino-1,2,4,5-tetrahydro-2-benzazepin-3-one (Aba) scaffolds has led to the discovery of novel potent μ-selective agonists (Structures 5 and 12) as well as potent and selective δ-opioid receptor antagonists (Structures 9 and 15). Both stereochemistry and N-terminal N,N-dimethylation proved to be crucial factors for opioid receptor selectivity and functional bioactivity in the investigated small peptidomimetic templates. In addition to the in vitro pharmacological evaluation, automated docking models of Dmt-Tic and Dmt-Aba analogues were constructed in order to rationalize the observed structure-activity data.
doi:10.1016/j.bmcl.2008.11.051
PMCID: PMC2742322  PMID: 19062273
19.  Inhibition of the Development of Morphine Tolerance by a Potent Dual μ-/δ-Opioid Antagonist, H-Dmt-Tic-Lys-NH-CH2-Ph 
Three analogues of the dual μ-/δ-antagonist, H-Dmt-Tic-R-NH-CH2-Ph (R = 1, Lys-Z; 2, Lys-Ac; 3, Lys) were examined in vivo: 1 and 2 exhibited weak bioactivity, while 3 injected intracerebroventricularly was a potent dual antagonist for morphine- and deltorphin C-induced antinociception comparable to naltrindole (δ-antagonist), but 93% as effective as naloxone (nonspecific opioid receptor antagonist) and 4% as active as CTOP, a μ antagonist. Subcutaneous or oral administration of 3 antagonized morphine-induced antinociception indicating passage across epithelial and blood-brain barriers. Mice pretreated with 3 before morphine did not develop morphine tolerance indicative of a potential clinical role to inhibit development of drug tolerance.
doi:10.1016/j.pbb.2008.05.008
PMCID: PMC2597683  PMID: 18571706
H-Dmt-Tic-Lys-NH-CH2-Ph; Antinociception; Tolerance; Spinal; Dual μ-/δ-opioid antagonist
20.  Activation of DOR Attenuates Anoxic K+ Derangement via Inhibition of Na+ Entry in Mouse Cortex 
Cerebral Cortex (New York, NY)  2008;18(9):2217-2227.
We have recently found that in the mouse cortex, activation of δ-opioid receptor (DOR) attenuates the disruption of K+ homeostasis induced by hypoxia or oxygen–glucose deprivation. This novel observation suggests that DOR may protect neurons from hypoxic/ischemic insults via the regulation of K+ homeostasis because the disruption of K+ homeostasis plays a critical role in neuronal injury under hypoxic/ischemic stress. The present study was performed to explore the ionic mechanism underlying the DOR-induced neuroprotection. Because anoxia causes Na+ influx and thus stimulates K+ leakage, we investigated whether DOR protects the cortex from anoxic K+ derangement by targeting the Na+-based K+ leakage. By using K+-sensitive microelectrodes in mouse cortical slices, we showed that 1) lowering Na+ concentration and substituting with impermeable N-methyl-D-glucamine caused a concentration-dependent attenuation of anoxic K+ derangement; 2) lowering Na+ concentration by substituting with permeable Li+ tended to potentiate the anoxic K+ derangement; and 3) the DOR-induced protection against the anoxic K+ responses was largely abolished by low-Na+ perfusion irrespective of the substituted cation. We conclude that external Na+ concentration greatly influences anoxic K+ derangement and that DOR activation likely attenuates anoxic K+ derangement induced by the Na+-activated mechanisms in the cortex.
doi:10.1093/cercor/bhm247
PMCID: PMC2517106  PMID: 18203692
anoxia; cortex; δ-opioid receptor; K+ homeostasis; Na+ influx; neuroprotection
21.  Synthesis of a potent and selective 18F-labeled δ-opioid receptor antagonist derived from the Dmt-Tic pharmacophore for PET imaging 
Journal of medicinal chemistry  2008;51(6):1817-1823.
H-Dmt-Tic-ε-Lys(Z)-OH (1) was used in the synthesis of 18F-labeled opioids for positron emission tomography (PET) imaging by coupling N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB) with Boc-Dmt-Tic-ε-Lys(Z)-OH under slightly basic conditions at 37 °C for 15 min, deprotected with TFA and HPLC purification in 120 min with a decay-corrected radiochemical 25–30% yield of [18F]-1 (n = 5) and specific activity ca. 46 GBq/µmol. Autoradiography uptake of [18F]-1 in striatum and cortex was blocked by 1 and UFP-501 demonstrating specific binding to δ-opioid receptors. MicroPET imaging revealed the absence of [18F]-1 in rat brain, suggesting its suitability for imaging peripheral δ-opioid receptors.
doi:10.1021/jm7014765
PMCID: PMC2667121  PMID: 18311909
22.  Role of Benzimidazole (Bid) in the δ Opioid Agonist Pseudopeptide H-Dmt-Tic-NH-CH2-Bid (UFP-502) 
Bioorganic & medicinal chemistry  2007;16(6):3032-3038.
H-Dmt-Tic-NH-CH2-Bid (UFP-502) was the first δ opioid agonist prepared from the Dmt-Tic pharmacophore. It showed interesting pharmacological properties, such as stimulation of mRNA BDNF expression, and antidepression. To evaluate the importance of 1H-benzimidazol-2-yl (Bid) in the induction of δ agonism, it was substituted by similar heterocycles: The substitution of NH(1) by O or S, transforms the reference δ agonist into δ antagonists. Phenyl ring of benzimidazole is not important for δ agonism; in fact 1H-imidazole-2-yl retains δ agonist activity.
doi:10.1016/j.bmc.2007.12.032
PMCID: PMC2390930  PMID: 18178091
23.  Conversion of the Potent δ-Opioid Agonist H-Dmt-Tic-NH-CH2-Bid into δ-Opioid Antagonists by N1-Benzimidazole Alkylation1 
Journal of medicinal chemistry  2005;48(26):8112-8114.
N1-Alkylation of 1H-benzimidizole of the δ agonist H-Dmt-Tic-NH-CH2-Bid with hydrophobic, aromatic, olefinic, acid, ethyl ester or amide (1–6) became δ antagonists (pA2 = 8.52–10.14). δ- and μ-Opioid receptor affinities were high (Kiδ = 0.12–0.36 nM and Kiμ = 0.44–1.42 nM). Only δ antagonism (pA2 = 8.52–10.14) was observed; μ agonism (IC50 = 30–450 nM) was not correlated with changes in alkylating agent or δ antagonism and some compounds yielded mixed δ antagonism/μ agonism.
doi:10.1021/jm058259l
PMCID: PMC2597450  PMID: 16366592
24.  A new opioid designed multiple ligand derived from the μ opioid agonist endomorphin-2 and the δ opioid antagonist pharmacophore Dmt-Tic 
Bioorganic & medicinal chemistry  2007;15(22):6876-6881.
Opioid compounds with mixed μ agonist / δ antagonist properties could be used as analgesics with low propensity to induce tolerance and dependence. Here we report the synthesis of a new designed multiple ligand deriving from the μ selective agonist endomorphin-2 and the δ selective antagonist pharmacophore Dmt-Tic. As predicted, the resulting bivalent ligand showed a μ agonist / δ antagonist profile deriving from the corresponding activities of each pharmacophore.
doi:10.1016/j.bmc.2007.08.047
PMCID: PMC2084217  PMID: 17851080
Designed multiple ligand; Endomorphin-2; Dmt-Tic pharmacophore; Analgesia; Physical dependence
25.  Effect of Lysine at C-Terminus of the Dmt-Tic Opioid Pharmacophore 
Journal of medicinal chemistry  2006;49(18):5610-5617.
Substitution of Gly with side-chain protected or unprotected Lys in lead compounds containing the opioid pharmacophore Dmt-Tic [H-Dmt-Tic-Gly-NH-CH2-Ph, μ agonist / δ antagonist; H-Dmt-Tic-Gly-NH-Ph, μ agonist / δ agonist and H-Dmt-Tic-NH-CH2-Bid, δ agonist (Bid = 1H-benzimidazole-2-yl)] yielded a new series of compounds endowed with distinct pharmacological activities. Compounds (1-10) included high δ- (Kiδ = 0.068-0.64 nM) and μ-opioid affinities (Kiδ = 0.13-5.50 nM) with a bioactivity that ranged from μ-opioid agonism {10, H-Dmt-Tic-NH-CH[(CH2)4-NH2]-Bid (IC50 GPI = 39.7 nM)} to a selective μ-opioid antagonist [3, H-Dmt-Tic-Lys-NH-CH2-Ph (pA2μ = 7.96)] and a selective δ-opioid antagonist [5, H-Dmt-Tic-Lys(Ac)-NH-Ph (pA2δ = 12.0)]. The presence of a Lys linker provides new lead compounds in the formation of opioid peptidomimetics containing the Dmt-Tic pharmacophore with distinct agonist and / or antagonist properties.
doi:10.1021/jm060741w
PMCID: PMC2533050  PMID: 16942034

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