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1.  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
2.  Delta opioidmimetic antagonists: prototypes for designing a new generation of ultraselective opioid peptides. 
Molecular Medicine  1995;1(6):678-689.
BACKGROUND: Tyr-Tic (1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid) and Tyr-Tic-Ala were the first peptides with delta opioid antagonist activity lacking Phe, considered essential for opioid activity based on the N-terminal tripeptide sequence (Tyr-D-Xaa-Phe) of amphibian skin opioids. Analogs were then designed to restrain the rotational flexibility of Tyr by the substitution of 2,6-dimethyl-L-tyrosine (Dmt). MATERIALS AND METHODS: Tyr and Dmt peptides were synthesized by solid phase and solution methods using Fmoc technology or condensing Boc-Dmt-OH or Boc-Tyr(But)-OH with H-L-Tic-OBut or H-D-Tic-OBut, respectively. Peptides were purified (> 99%) by HPLC and characteristics determined by 1H-NMR, FAB-MS, melting point, TLC, and amino acid analyses. RESULTS: H-Dmt-Tic-OH had high affinity (Ki delta = 0.022 nM) and extraordinary selectivity (Ki mu/Ki delta = 150,000); H-Dmt-Tic-Ala-OH had a Ki delta = 0.29 nM and delta selectivity = 20,000. Affinity and selectivity increased 8700- and 1000-fold relative to H-Tyr-Tic-OH, respectively. H-Dmt-Tic-OH and H-Dmt-Tic-NH2 fitted one-site receptor binding models (eta = 0.939-0.987), while H-Dmt-Tic-ol, H-Dmt-Tic-Ala-OH and H-Dmt-Tic-Ala-NH2 best fitted two-site models (eta = 0.708-0.801, F 18.9-26.0, p < 0.0001). Amidation increased mu affinity by 10- to 100-fold and acted synergistically with D-Tic2 to reverse selectivity (delta-->mu). Dmt-Tic di- and tripeptides exhibited delta antagonist bioactivity (Ke = 4-66 nM) with mouse vas deferens and lacked agonist mu activity (> 10 microM) in guinea-pig ileum preparations. Dmt-Tic analogs weakly interacted with kappa receptors in the 1 to > 20 microM range. CONCLUSIONS: Dmt-Tic opioidmimetic peptides represent a highly potent class of opioid peptide antagonists with greater potency than the nonopioid delta antagonist naltrindole and have potential application as clinical and therapeutic compounds.
PMCID: PMC2229973  PMID: 8529134
3.  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
4.  Further Studies on the Effect of Lysine at the C-Terminus of the Dmt-Tic Opioid Pharmacophore 
Bioorganic & medicinal chemistry  2007;15(9):3143-3151.
A wide range of bioactivities are induced by Lys when introduced at the C-terminus of the δ-opioid Dmt-Tic pharmacophore through the α-amine group, such as improved δ-antagonism, and presence of μ-agonism and μ-antagonism. We report the synthesis of a new series of compounds with the general formula H-Dmt-Tic-NH-(CH2)4-CH(R)-R’ (R = -NH2, -NH-Ac, -NH-Z; R’ = CO-NH-Ph, -CO-NH-CH2-Ph, -Bid) in which Lys is linked to Dmt-Tic through its amine group side chain. The compounds (1-9) displayed a potent and selective δ-antagonism (pA2 = 7.81-8.27) independent of the functionalized α-amine and carboxylic groups of the C-terminal Lys. This suggests direct application as a prototype intermediate, such as Boc-Dmt-Tic-ε-Lys(Z)-OMe, which could be applied in the synthesis (after Z or methyl ester removal) of unique “designed multiple ligands” containing the pharmacophore of the quintessential δ-antagonist Dmt-Tic and another opioid or biologically active non-opioid ligand.
doi:10.1016/j.bmc.2007.02.039
PMCID: PMC2377021  PMID: 17339114
5.  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
6.  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
7.  An Engineered Knottin Peptide Labeled with 18F for PET Imaging of Integrin Expression 
Bioconjugate chemistry  2009;20(12):2342-2347.
Knottins are small constrained polypeptides that share a common disulfide-bonded framework and a triple-stranded β-sheet fold. Previously, directed evolution of the Ecballium elaterium trypsin inhibitor (EETI-II) knottin led to the identification of a mutant that bound to tumor-specific αvβ3 and αvβ5 integrin receptors with low nanomolar affinity. The objective of this study was to prepare and evaluate a radiofluorinated version of this knottin (termed 2.5D) for microPET imaging of integrin positive tumors in living subjects. Knottin peptide 2.5D was prepared by solid phase synthesis and folded in vitro, and its free N-terminal amine was reacted with N-succinimidyl-4-18/19F-fluorobenzoate (18/19F-SFB) to produce the fluorinated peptide 18/19F-FB-2.5D. The binding affinities of unlabeled knottin peptide 2.5D and 19F-FB-2.5D to U87MG glioblastoma cells were measured by competition binding assay using 125I-labeled echistatin. It was found that unlabeled 2.5D and 19F-FB-2.5D competed with 125I-echistatin for binding to cell surface integrins with IC50 values of 20.3 ± 7.3 and 13.2 ± 5.4 nM, respectively. Radiosynthesis of 18F-FB-2.5D resulted in a product with high specific activity (ca 100 GBq/μmol). Next, biodistribution and positron emission tomography (PET) imaging studies were performed to evaluate the in vivo behavior of 18F-FB-2.5D. Approximately 3.7 MBq 18F-FB-2.5D was injected into U87MG tumor bearing mice via the tail vein. Biodistribution studies demonstrated that 18F-FB-2.5D had moderate tumor uptake at 0.5 h post injection, and co-injection of a large excess of the unlabeled peptidomimetic c(RGDyK) as a blocking agent significantly reduced tumor uptake (1.90 ± 1.15 vs. 0.57 ± 0.14 %ID/g, 70% inhibition, P < 0.05). In vivo microPET imaging showed that 18F-FB-2.5D rapidly accumulated in the tumor and quickly cleared from the blood through the kidneys, allowing excellent tumor-to-normal tissue contrast to be obtained. Collectively, 18F-FB-2.5D allows integrin-specific PET imaging of U87MG tumors with good contrast, and further demonstrates that knottins are excellent peptide scaffolds for development of PET probes with potential for clinical translation.
doi:10.1021/bc900361g
PMCID: PMC2804269  PMID: 19908826
Kottin Peptide; Integrin; 18F; PET; RGD
8.  Opioid and Melanocortin Receptors: Do They Have Opioid Overlapping Pharmacophores? 
Biopolymers  2008;90(3):433-438.
We have identified compound 1 as a novel ligand for opioid and melanocortin (MC) receptors, which is derived from the overlapping of a well known structure for the δ opioid receptor, 2,6-dimethyltyrosine (Dmt)-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (Tic), and a small molecule for the MC receptor, Tic-DPhe(p-Cl)-piperidin-4-yl-N-phenyl-propionamide. Ligand 1 showed that there is an overlapping pharmacophore between opioid and MC receptors through the Tic residue. The ligand displayed high biological activities at the δ opioid receptor (Ki = 0.38 nM in binding assay, EC50 = 0.48 nM in GTP-γ-S binding assay, IC50 = 74 nM in MVD) as an agonist instead of an antagonist and showed selective binding affinity (IC50 = 2.3 μM) at the MC-3 receptor rather than at the MC-5 receptor. A study of the structure-activity relationships demonstrated that the residues in positions 2, 3, and the C-terminus act as a pharmacophore for the MC receptors, and the residues in positions 1 and 2 act as a pharmacophore for the opioid receptors. Thus, this structural construct can be used to prepare chimeric structures with adjacent or overlapping pharmacophores for opioid and MC receptors.
doi:10.1002/bip.20814
PMCID: PMC2693099  PMID: 17657709
opioid receptor; melanocortin receptor; anti-opioid effect; multi-target drug; overlapping pharmacophores; antinociception; side effect; Dmt-Tic; fentanyl
9.  A Thiol-Reactive 18F-Labeling Agent, N-[2-(4-18F-Fluorobenzamido)Ethyl]Maleimide, and Synthesis of RGD Peptide-Based Tracer for PET Imaging of αvβ3 Integrin Expression 
The cell adhesion molecule integrin αvβ3 plays a key role in tumor angiogenesis and metastasis. A series of 18F-labeled RGD peptides have been developed for PET of integrin expression based on primary amine-reactive prosthetic groups. In this study we introduced a new method of labeling RGD peptides through a thiol-reactive synthon, N-[2-(4-18F-fluorobenzamido)ethyl]maleimide (18F-FBEM).
Methods
18F-FBEM was synthesized by coupling N-succinimidyl 4-18F-fluorobenzoate (18F-SFB) with N-(2-aminoethyl)maleimide. After high-pressure liquid chromatography purification, it was allowed to react with thiolated RGD peptides, and the resulting tracers were subjected to receptor-binding assay, in vivo metabolic stability assessment, biodistribution, and microPET studies in murine xenograft models.
Results
Conjugation of monomeric and dimeric sulfhydryl-RGD peptides with 18F-FBEM was achieved in high yields (85% ± 5% nondecay-corrected on the basis of 18F-FBEM). The radiochemical purity of the 18F-labeled peptides was >98% and the specific activity was 100~ 150 TBq/mmol. Noninvasive microPET and direct tissue sampling experiments demonstrated that both 18F-FBEM-SRGD (RGD monomer) and 18F-FBEM-SRGD2 (RGD dimer) had integrin-specific tumor uptake in subcutaneous U87MG glioma and orthotopic MDA-MB-435 breast cancer xenografts.
Conclusion
The new tracer 18F-FBEM-SRGD2 was synthesized with high specific activity via 18F-FBEM and the tracer exhibited high receptor-binding affinity, tumor-targeting efficacy, metabolic stability, as well as favorable in vivo pharmacokinetics. The new synthon 18F-FBEM developed in this study will also be useful for radiolabeling of other thiolated biomolecules.
PMCID: PMC1704081  PMID: 16818952
thiol-reactive synthon; 18F-FBEM; microPET; 18F labeling; integrin αvβ3
10.  Solid-Phase Synthetic Strategy & Bioevaluation of a Labeled δ-Opioid Receptor Ligand Dmt-Tic-Lys for In Vivo Imaging 
Organic letters  2009;11(12):2479-2482.
A general solid-phase synthetic strategy is developed to prepare fluorescent and/or lanthanide labeled derivatives of the δ-opioid receptor (δOR) ligand H-Dmt-Tic-Lys(R)-OH. The high δ-OR affinity (Ki = 3 nM) and desirable in vivo characteristics of the Cy5 derivative 1 suggests its usefulness for structure-function studies, receptor localization and as a high-contrast non-invasive molecular marker for live imaging ex vivo or in vivo.
doi:10.1021/ol900200k
PMCID: PMC2756606  PMID: 19445485
11.  F-18 Labeled Vasoactive Intestinal Peptide Analogue in the PET Imaging of Colon Carcinoma in Nude Mice 
BioMed Research International  2013;2013:420480.
As large amount of vasoactive intestinal peptide (VIP) receptors are expressed in various tumors and VIP-related diseases, radiolabeled VIP provides a potential PET imaging agent for VIP receptor. However, structural modification of VIP is required before being radiolabeled and used for VIP receptor imaging due to its poor in vivo stability. As a VIP analogue, [R8, 15, 21, L17]-VIP exhibited improved stability and receptor specificity in preliminary studies. In this study, F-18 labeled [R8,15,21, L17]-VIP was produced with the radiochemical yield being as high as 33.6% ± 3% (decay-for-corrected, n = 5) achieved within 100 min, a specific activity of 255 GBq/μmol, and a radiochemical purity as high as 99% as characterized by radioactive HPLC, TLC, and SDS-Page radioautography. A biodistribution study in normal mice also demonstrated fast elimination of F-18 labeled [R8,15,21, L17]-VIP in the blood, liver, and gastrointestinal tracts. A further micro-PET imaging study in C26 colon carcinoma bearing mice confirmed the high tumor specificity, with the tumor/muscle radioactivity uptake ratio being as high as 3.03 at 60 min following injection, and no apparent radioactivity concentration in the intestinal tracts. In addition, blocking experiment and Western Blot test further confirmed its potential in PET imaging of VIP receptor-positive tumor.
doi:10.1155/2013/420480
PMCID: PMC3888718  PMID: 24459669
12.  Radiofluorinated Rhenium Cyclized α-MSH Analogs for PET Imaging of Melanocortin Receptor 1 
Bioconjugate chemistry  2010;21(12):2355-2360.
In order to accomplish in vivo molecular imaging of melanoma biomarker melanocortin 1 receptor (MC1R), several alpha-melanocyte-stimulating hormone (α-MSH) analogs have been labeled with N-succinimidyl-4-18F-fluorobenzoate (18F-SFB) and studied as positron emission tomography (PET) probes in our recent studies. To further pursue a radiofluorinated α-MSH peptide with high clinical translation potential, we utilized 4-nitrophenyl 2-18F-fluoropropionate (18F-NFP) to radiofluorinate the transition metal rhenium cyclized α-MSH metallopeptides for PET imaging of MC1R positive malignant melanoma.
Methods
Metallopeptides Ac-d,Lys-ReCCMSH(Arg11) (two isomers, namely RMSH-1 and RMSH-2) were synthesized using conventional solid phase peptide synthesis chemistry and rhenium cyclization reaction. The two isomers were then conjugated with 19F-NFP or 18F-NFP. The resulting cold or radiofluorinated metallopeptides, 18/19F-FP-RMSH-1 and 18/19F-FP-RMSH-2 were further evaluated for their in vitro receptor binding affinities, in vivo biodistribution and small-animal PET imaging properties.
Results
The binding affinities of the 19F-FP-RMSH-1 and 19F-FP-RMSH-2) were determined to be within low nM range. In vivo studies revealed that both 18F-labeled metallopeptides possessed good tumor uptake in B16F10 murine model with high MC1R expression, while much lower uptake in A375M human melanoma xenografts. Moreover, 18F-FP-RMSH-1 displayed more favorable in vivo performance in terms of higher tumor uptake and much lower accumulation in kidney and liver, when compared to 18F-FP-RMSH-2 at 2 h post-injection (p.i.). 18F-FP-RMSH-1 also displayed lower liver and lung uptake when compared with the same peptide labeled with 18F-SFB (named as 18F-FB-RMSH-1). Small animal PET imaging of 18F-FP-RMSH-1 in mice bearing B16F10 tumors at 1 and 2 h showed good tumor imaging quality. As expected, much lower tumor uptake and poorer tumor/normal organs contrast were observed for A375M model than that of B16F10 model. 18F-FP-RMSH-1 also exhibited higher tumor uptake and better tumor retention when compared with 18F-FB-RMSH-1.
Conclusion
18F-FP-RMSH-1 demonstrates significant advantages over 18F-FB-RMSH-1 and 18F-FP-RMSH-2. It is a promising PET probe for imaging MC1R positive melanoma and MC1R expression in vivo.
doi:10.1021/bc100391a
PMCID: PMC3046310  PMID: 21073170
α-MSH; MC1R; PET; Malignant Melanoma; Metallopeptide, 18F
13.  Biodistribution and Elimination Study of Fluorine-18 Labeled Nε-Carboxymethyl-Lysine following Intragastric and Intravenous Administration 
PLoS ONE  2013;8(3):e57897.
Background
Nε-carboxymethyl-lysine (CML) is a major advanced glycation end-product (AGEs) widely found in foods. The aim of our study was to evaluate how exogenous CML-peptide is dynamically absorbed from the gastrointestinal tract and eliminated by renal tubular secretion using microPET imaging.
Methods
The present study consisted of three investigations. In study I, we synthesized the imaging tracer 18F-CML by reacting N-succinimidyl 4-18F-fluorobenzoate (18F-SFB) with CML. In study II, the biological activity of 18F-CML was evaluated in RAW264.7 cells and HepG2 cells. In study III, the biodistribution and elimination of AGEs in ICR mice were studied in vivo following tail vein injection and intragastric administration of 18F-CML.
Result
The formation of 18F-CML was confirmed by comparing its retention time with the corresponding reference compound 19F-CML. The radiochemical purity (RCP) of 18F-CML was >95%, and it showed a stable character in vitro and in vivo. Uptake of 18F-CML by RAW264.7 cells and HepG2 cells could be inhibited by unmodified CML. 18F-CML was quickly distributed via the blood, and it was rapidly excreted through the kidneys 20 min after tail vein injection. However, 18F-CML was only slightly absorbed following intragastric administration. After administration of 18F-CML via a stomach tube, the radioactivity was completely localized in the stomach for the first 15 min. At 150 min post intragastric administration, intense accumulation of radioactivity in the intestines was still observed.
Conclusions
PET technology is a powerful tool for the in vivo analysis of the gastrointestinal absorption of orally administered drugs. 18F-CML is hardly absorbed by the gastrointestinal tract. It is rapidly distributed and eliminated from blood following intravenous administration. Thus, it may not be harmful to healthy bodies. Our study showed the feasibility of noninvasively imaging 18F-labeled AGEs and was the first to describe CML-peptide gastrointestinal absorption by means of PET.
doi:10.1371/journal.pone.0057897
PMCID: PMC3591457  PMID: 23505446
14.  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
15.  Bifunctional μ/δ Opioid Peptides: Variation of the Type and Length of the Linker Connecting the Two Components 
Chemical biology & drug design  2012;79(2):186-193.
On the basis of evidence that opioid compounds with a mixed μ agonist/δ antagonist profile may produce an antinociceptive effect with low propensity to induce side effects, bifunctional opioid peptides containing the μ agonist [Dmt1]DALDA (H-Dmt-D-Arg-Phe-Lys-NH2; Dmt = 2',6’-dimethyltyrosine) connected tail-to-tail via various α,ω-diaminoalkyl- or diaminocyclohexane linkers to the δ antagonists TICP[Ψ] (H-Tyr-TicΨ[CH2-NH]Cha-Phe-OH; Cha = cyclohexylalanine, Tic = 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid), H-Dmt-Tic-OH or H-Bcp-Tic-OH (Bcp = 4'-[N-((4'-phenyl)phenethyl)carboxamido]phenylalanine) were synthesized and pharmacologically characterized in vitro. Bifunctional [Dmt1]DALDA→NH-(CH2)n-NH←TICP[Ψ] compounds (n = 0–12) showed decreasing μ and δ receptor binding affinities with increasing linker length. As expected, several of the bifunctional peptides were μ agonist/δ antagonists with low nanomolar μ and δ receptor binding affinities. However, compounds with unexpected opioid activity profiles, including a μ partial agonist/δ partial agonist, μ antagonist/δ antagonists and μ agonist/δ agonists, were also identified. These results indicate that the binding affinities and intrinsic efficacies of these bifunctional compounds at both receptors depend on the length and type of the linker connecting the μ and δ components. An important recommendation emerging from this study is that the in vitro activity profiles of bifunctional compounds containing an agonist and an antagonist component connected via a linker need to be determined prior to their pharmacological evaluation in vivo.
doi:10.1111/j.1747-0285.2011.01268.x
PMCID: PMC3253174  PMID: 22070627
opioid peptide analogues; peptide synthesis; bifunctional μ/δ opioid compounds; opioid activity profiles; opioid peptide SAR; linkers in bifunctional opioid peptides
16.  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
17.  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
18.  New Opioid Designed Multiple Ligand from Dmt-Tic and Morphinan Pharmacophores 
Journal of medicinal chemistry  2006;49(18):5640-5643.
Here we report the facile synthesis of a designed multi-pharmacophore ligand derived from the linkage of a delta selective peptide antagonist (Dmt-Tic) and a mu / kappa morphinan agonist butorphan (MCL 101) through a two methylene spacer. The new compound MCL 450 maintains the same characteristics as the two reference compounds. MCL 450 represents a useful starting point for the synthesis of other multiple opioid ligands endowed with analgesic properties with low tolerance and dependence.
doi:10.1021/jm0605785
PMCID: PMC2435260  PMID: 16942040
19.  The Hallucinogen N,N-Dimethyltryptamine (DMT) Is an Endogenous Sigma-1 Receptor Regulator 
Science (New York, N.Y.)  2009;323(5916):934-937.
The sigma-1 receptor is widely distributed in the central nervous system and periphery. Originally mischaracterized as an opioid receptor, the sigma-1 receptor binds a vast number of synthetic compounds but does not bind opioid peptides; it is currently considered an orphan receptor. The sigma-1 receptor pharmacophore includes an alkylamine core, also found in the endogenous compound N,N-dimethyltryptamine (DMT). DMT acts as a hallucinogen, but its receptor target has been unclear. DMT bound to sigma-1 receptors and inhibited voltage-gated sodium ion (Na+) channels in both native cardiac myocytes and heterologous cells that express sigma-1 receptors. DMT induced hypermobility in wild-type mice but not in sigma-1 receptor knockout mice. These biochemical, physiological, and behavioral experiments indicate that DMT is an endogenous agonist for the sigma-1 receptor.
doi:10.1126/science.1166127
PMCID: PMC2947205  PMID: 19213917
20.  5-(5-(6-[11C]methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)pyridin-2-yl)-1H-indole as a potential PET radioligand for imaging cerebral α7-nAChR in mice 
Bioorganic & medicinal chemistry  2012;20(12):3698-3702.
The radiosynthesis and in vivo evaluation of 5-(5-(6-[11C]methyl-3,6-diazabicyclo[3.2.0]heptan-3-yl)pyridin-2-yl)-1H-indole [11C]rac-(1), a potential PET tracer for α7 nicotinic acetylcholine receptors (α7-nAChR), are described. Syntheses of the nonradioactive standard rac-1 and corresponding desmethyl precursor 7 were achieved in several reaction steps. Radiomethylation of 7 with [11C]CH3I afforded [11C]rac-1 in an average radiochemical yield of 30 ± 5% (n = 5) with high radiochemical purity and an average specific radioactivity of 444 ± 74 GBq/µmol (n = 5). The total synthesis time was 30 min from end-of-bombardment. Biodistribution studies in mice showed that [11C]rac-1 penetrates the blood-brain barrier and specifically labels neuronal α7-nAChRs.
doi:10.1016/j.bmc.2012.04.056
PMCID: PMC3527104  PMID: 22608919
positron emission tomography; radioligand; nicotinic acetylcholine receptors; α7-nAChR
21.  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
22.  N-Succinimidyl 4-[18F]-fluoromethylbenzoate-labeled dimeric RGD peptide for imaging tumor integrin expression 
Amino acids  2011;43(3):1349-1357.
RGD peptides, radiolabeled with 18F, have been used in the clinic for PET imaging of tumor angiogenesis in cancer patients. RGD peptides are typically labeled using a prosthetic group such as N-succinimidyl 4-[18F]-fluorobenzoate ([18F]SFB) or 4-nitrophenyl 2-[18F]-fluoropropionate ([18F]NPFP). However, the complex radiosynthetic procedures have impeded their broad application in clinical studies. We previously radiolabeled proteins and peptides with the prosthetic group, N-succinimidyl 4-[18F]-fluoromethylbenzoate ([18F]SFMB), which was prepared in a simple one-step procedure. In this study, we labeled a PEGylated cyclic RGD peptide dimer, PEG3-E[c(RGDy K)]2 (PRGD2), using [18F]SFMB and evaluated for imaging tumor αvβ3 integrin expression with positron emission tomography (PET). [18F]SFMB was prepared in one step using [18F]fluoride displacement of a nitrobenzenesulfonate leaving group under mild reaction conditions followed by HPLC purification. The 18F-labeled peptide, [18F]FMBPR GD2 was prepared by coupling PRGD2 with [18F]SFMB in pH 8.6 borate buffer and purified with HPLC. The direct labeling on BMBPRGD2 was also attempted. A Siemens Inveon PET was used to image the uptake of the [18F]FMBPRGD2 into a U87MG xenograft mouse model. [18F]FMBPRGD2, was prepared with a 15% overall radiochemical yield (uncorrected) in a total synthesis time of 90 min, which was considerably shorter than the preparation of [18F]SFB- and [18F]NPFP-labeled RGD peptides. The direct labeling, however, was not successful. High quality microPET images using [18F]FMBPRGD2 clearly visualized tumors by 15 min with good target to background ratio. Early tracer accumulation in the bladder suggests fast renal clearance. No obvious bone uptake can be detected even at 4-h time point indicating that fluorine attachment is stable in mice. In conclusion, N-succinimidyl 4-[18F]-fluoromethylbenzoate ([18F]SFMB) prosthetic group can be a good alternative for labeling RGD peptides to image αvβ3 integrin expression and for labeling other peptides.
doi:10.1007/s00726-011-1208-4
PMCID: PMC3577934  PMID: 22209865
Integrin αvβ3; RGD peptide dimer; Positron emission tomography; N-Succinimidyl 4-[18F]-fluoromethylbenzoate ([18F]SFMB)
23.  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
24.  Radiosynthesis and in vivo evaluation of [11C]MP-10 as a PET probe for imaging PDE10A in rodent and nonhuman primate brain 
Bioorganic & medicinal chemistry  2011;19(5):1666-1673.
2-((4-(1-[11C]methyl-4-(pyridin-4-yl)-1H-pyrazol-3-yl)phenoxy)methyl)-quinoline (MP-10), a specific PDE10A inhibitor (IC50 = 0.18 nM with 100-fold selectivity over other PDEs), was radiosynthesized by alkylation of the desmethyl precursor with [11C]CH3I, ~45% yield, > 92% radiochemical purity, > 370 GBq/μmol specific activity at end of bombardment (EOB). Evaluation in Sprague-Dawley rats revealed that [11C]MP-10 had highest brain accumulation in the PDE10A enriched striatum, the 30 min striatum: cerebellum ratio reached 6.55. MicroPET studies of [11C]MP-10 in monkeys displayed selective uptake in striatum. However, a radiolabeled metabolite capable of penetrating the blood brain barrier may limit the clinical utility of [11C]MP-10 as a PDE10A PET tracer.
doi:10.1016/j.bmc.2011.01.032
PMCID: PMC3056285  PMID: 21315609
PDE10A; PET imaging; carbon-11; MP-10; Huntington’s disease
25.  6-N,N-Dimethylamino-2,3-Naphthalimide a New Environment-Sensitive Fluorescent Probe in δ-Selective and μ-Selective Opioid Peptides 
Journal of medicinal chemistry  2006;49(12):3653-3658.
A new environment-sensitive fluorophore, 6-N,N-dimethylamino-2,3-naphthalimide (6DMN) was introduced in the δ-selective opioid agonist H-Dmt-Tic-Glu-NH2 and in the μ-selective opioid agonist endomorphin-2 (H-Tyr-Pro-Phe-Phe-NH2). Environment sensitive fluorophores are a special class of chromophores that generally exhibit a low quantum yield in aqueous solution, but become highly fluorescent in nonpolar solvents or when bound to hydrophobic sites in proteins or membranes. New fluorescent δ-selective irreversible antagonists [H-Dmt-Tic-Glu-NH-(CH2)5-CO-Dap(6DMN)-NH2(1) and H-Dmt-Tic-Glu-Dap(6DMN)-NH2)] (2) were identified as potential fluorescent probes showing properties suitable for studies of distribution and internalization of δ-opioid receptors by confocal laser scanning microscopy.
doi:10.1021/jm060343t
PMCID: PMC1994907  PMID: 16759107

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