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1.
ChemMedChem ; 12(8): 571-576, 2017 04 20.
Article in English | MEDLINE | ID: mdl-28296145

ABSTRACT

We describe the design, synthesis, and opioid activity of fluoroalkene (Tyr1 -ψ[(Z)CF=CH]-Gly2 ) and trifluoroethylamine (Tyr1 -ψ[(S)/(R)-CF3 CH-NH]-Gly2 ) analogues of the endogenous opioid neuropeptide, Leu-enkephalin. The fluoroalkene peptidomimetic exhibited low nanomolar functional activity (5.0±2 nm and 60±15 nm for δ- and µ-opioid receptors, respectively) with a µ/δ-selectivity ratio that mimics that of the natural peptide. However, the trifluoroethylamine peptidomimetics, irrespective of stereochemistry, did not activate the opioid receptors, which suggest that bulky CF3 substituents are not tolerated at this position.


Subject(s)
Analgesics, Opioid/pharmacology , Enkephalin, Leucine/analogs & derivatives , Hydrocarbons, Fluorinated/pharmacology , Peptidomimetics/pharmacology , Analgesics, Opioid/chemical synthesis , Animals , CHO Cells , Cricetulus , Enkephalin, Leucine/chemical synthesis , Enkephalin, Leucine/pharmacology , Humans , Hydrocarbons, Fluorinated/chemical synthesis , Peptidomimetics/chemical synthesis , Receptors, Opioid/agonists , Stereoisomerism , Structure-Activity Relationship
2.
ACS Chem Neurosci ; 4(8): 1204-16, 2013 Aug 21.
Article in English | MEDLINE | ID: mdl-23650868

ABSTRACT

Leu-enkephalin analogues, in which the amide bonds were sequentially and systematically replaced either by ester or N-methyl amide bonds, were prepared using classical organic chemistry as well as solid phase peptide synthesis (SPPS). The peptidomimetics were characterized using competition binding, ERK1/2 phosphorylation, receptor internalization, and contractility assays to evaluate their pharmacological profile over the delta opioid receptor (DOPr). The lipophilicity (LogD7.4) and plasma stability of the active analogues were also measured. Our results revealed that the last amide bond can be successfully replaced by either an ester or an N-methyl amide bond without significantly decreasing the biological activity of the corresponding analogues when compared to Leu-enkephalin. The peptidomimetics with an N-methyl amide function between residues Phe and Leu were found to be more lipophilic and more stable than Leu-enkephalin. Findings from the present study further revealed that the hydrogen-bond donor properties of the fourth amide of Leu-enkephalin are not important for its biological activity on DOPr. Our results show that the systematic replacement of amide bonds by isosteric functions represents an efficient way to design and synthesize novel peptide analogues with enhanced stability. Our findings further suggest that such a strategy can also be useful to study the biological roles of amide bonds.


Subject(s)
Enkephalin, Leucine/analogs & derivatives , Peptidomimetics/pharmacology , Receptors, Opioid, delta/metabolism , Amides/pharmacology , Animals , Depsipeptides/chemical synthesis , Depsipeptides/pharmacology , Enkephalin, Leucine/chemical synthesis , Esters/chemical synthesis , Esters/pharmacology , Hydrogen Bonding , Male , Mice , Peptidomimetics/chemical synthesis , Receptors, Opioid, delta/drug effects , Solid-Phase Synthesis Techniques/methods , Vas Deferens/drug effects
3.
J Org Chem ; 78(8): 3541-52, 2013 Apr 19.
Article in English | MEDLINE | ID: mdl-23373789

ABSTRACT

Novel N-(N-Pg-azadipeptidoyl)benzotriazoles 20a-e couple efficiently with α-amino acids 21a-e, dipeptides 22a-c, aminoxyacetic acid 23a, depsidipeptide 23b, and α-hydroxy-ß-phenylpropionic acid 27 yielding, respectively, azatripeptides 24a-g, azatetrapeptides 25a,b, a hybrid azatripeptide with an oxyamide bond 26a, a hybrid azatetrapeptide with an ester bond 26b, and a hybrid azatripeptide with an ester bond 28. A new protocol for the synthesis of N-Pg-azatripeptides 33a,b and 35a,b, each containing a natural amino acid at the N-terminus, avoids the low coupling rates of the aza-amino acid residue and enables the solution-phase synthesis of an azaphenylalanine analogue of Leu-enkephalin 40.


Subject(s)
Amino Acids/chemistry , Amino Acids/chemical synthesis , Aza Compounds/chemical synthesis , Dipeptides/chemical synthesis , Enkephalin, Leucine/chemistry , Enkephalin, Leucine/chemical synthesis , Peptides/chemistry , Peptides/chemical synthesis , Propionates/chemical synthesis , Triazoles/chemistry , Amino Acid Sequence , Aza Compounds/chemistry , Dipeptides/chemistry , Molecular Structure , Propionates/chemistry
4.
J Org Chem ; 77(22): 9954-8, 2012 Nov 16.
Article in English | MEDLINE | ID: mdl-23116417

ABSTRACT

A novel linker for the synthesis of C-terminal acetylene-functionalized protected peptides is described. This SAM1 linker is applied in the manual Fmoc-based solid-phase peptide synthesis of Leu-enkephalin and in microwave-assisted automated synthesis of Maculatin 2.1, an antibacterial peptide that contains 18 amino acid residues. For the cleavage, treatment with tetramethylammonium fluoride results in protected acetylene-derivatized peptides. Alternatively, a one-pot cleavage-click procedure affords the protected 1,2,3-triazole conjugate in high yields after purification.


Subject(s)
Acetylene/chemistry , Acetylene/chemical synthesis , Alkynes/chemistry , Enkephalin, Leucine/chemistry , Enkephalin, Leucine/chemical synthesis , Peptides/chemistry , Peptides/chemical synthesis , Silanes/chemistry , Microwaves , Molecular Structure , Solid-Phase Synthesis Techniques
5.
J Pept Sci ; 17(7): 487-92, 2011 Jul.
Article in English | MEDLINE | ID: mdl-21495120

ABSTRACT

Regulatory pressure has compelled the chemical manufacturing industry to reduce the use of organic solvents in synthetic chemistry, and there is currently a strong focus on replacing these solvents with water. Here, we describe an efficient in-water solution-phase peptide synthesis method using Boc-amino acids. It is based on a coupling reaction utilizing suspended water-dispersible nanoparticle reactants. Using this method, peptides were obtained in good yield and with high purity.


Subject(s)
Amino Acids/chemistry , Formic Acid Esters/chemistry , Nanoparticles/chemistry , Peptides/chemistry , Peptides/chemical synthesis , Water/chemistry , Chromatography, High Pressure Liquid , Enkephalin, Leucine/analogs & derivatives , Enkephalin, Leucine/chemical synthesis , Enkephalin, Leucine/chemistry , Molecular Structure , Solutions/chemistry , Solvents/chemistry
6.
ACS Chem Neurosci ; 1(11): 757-69, 2010 Nov 17.
Article in English | MEDLINE | ID: mdl-22778812

ABSTRACT

The role of each of the four amide bonds in Leu(5)-enkephalin was investigated by systematically and sequentially replacing each with its corresponding trans-alkene. Six Leu(5)-enkephalin analogs based on six dipeptide surrogates and two Met(5)-enkephalin analogs were synthesized and thoroughly tested using a δ-opioid receptor internalization assay, an ERK1/2 activation assay, and a competition binding assay to evaluate their biological properties. We observed that an E-alkene can efficiently replace the first amide bond of Leu(5)- and Met(5)-enkephalin without significantly affecting biological activity. By contrast, the second amide bond was found to be highly sensitive to the same modification, suggesting that it is involved in biologically essential intra- or intermolecular interactions. Finally, we observed that the affinity and activity of analogs containing an E-alkene at either the third or fourth position were partially reduced, indicating that these amide bonds are less important for these intra- or intermolecular interactions. Overall, our study demonstrates that the systematic and sequential replacement of amide bonds by E-alkene represents an efficient way to explore peptide backbones.


Subject(s)
Enkephalins/chemistry , Enkephalins/pharmacology , Receptors, Opioid, delta/drug effects , Animals , Binding, Competitive/drug effects , Cell Line , Enkephalin, Leucine/analogs & derivatives , Enkephalin, Leucine/chemical synthesis , Enkephalin, Leucine/pharmacology , Enkephalin, Methionine/analogs & derivatives , Enkephalin, Methionine/chemical synthesis , Enkephalin, Methionine/pharmacology , Indicators and Reagents , Mice , Mitogen-Activated Protein Kinases/metabolism , Models, Molecular , Molecular Conformation , Receptors, Opioid, delta/agonists , Receptors, Opioid, delta/metabolism , Signal Transduction/drug effects , Structure-Activity Relationship
7.
J Pept Sci ; 15(11): 777-82, 2009 Nov.
Article in English | MEDLINE | ID: mdl-19787815

ABSTRACT

beta-Amino acids containing hybrid peptides and beta-peptides show great potential as peptidomimetics. In this paper we describe the synthesis and affinity toward the micro- and delta-opioid receptors of beta-peptides, analogues of Leu-enkephalin, deltorphin I, dermorphin and alpha,beta-hybrides, analogues of deltorphin I. Substitution of alpha-amino acid residues with beta(3)-homo-amino acid residues, in general resulted in decrease of affinity to opioid receptors. However, the incorporation beta(3)h-D-Ala in position 2 or beta(3)hPhe in position 3 of deltorphin I resulted in potent and selective ligand for delta-opioid receptor. The NMR studies of beta-deltorphin I analogue suggest that conformational motions in the central part of the peptide backbone are partially restricted and some conformational preferences can be expected.


Subject(s)
Opioid Peptides/metabolism , Receptors, Opioid/metabolism , Enkephalin, Leucine/chemical synthesis , Enkephalin, Leucine/chemistry , Enkephalin, Leucine/metabolism , Magnetic Resonance Spectroscopy , Molecular Structure , Oligopeptides/chemical synthesis , Oligopeptides/chemistry , Oligopeptides/metabolism , Opioid Peptides/chemical synthesis , Opioid Peptides/chemistry , Protein Binding , Receptors, Opioid, mu/metabolism , Receptors, sigma/metabolism , Structure-Activity Relationship
8.
J Org Chem ; 74(5): 2028-32, 2009 Mar 06.
Article in English | MEDLINE | ID: mdl-19196166

ABSTRACT

Microwave-assisted solid-phase syntheses of six "difficult" peptides, H-VVSVV-NH(2) (3), H-VVVSVV-NH(2) (4), H-VIVIG-OH (5), H-TVTVTV-NH(2) (6), H-VKDGYI-NH(2) (7), and H-VKDVYI-NH(2) (8), were achieved utilizing N-(Fmoc-alpha-aminoacyl)benzotriazoles. Extension to the syntheses of Leu-enkephalin (9) and amyloid-beta (34-42) (10) demonstrates that this strategy comprises an efficient route to new and known "difficult" peptides.


Subject(s)
Amyloid beta-Peptides/chemical synthesis , Enkephalin, Leucine/chemical synthesis , Peptide Fragments/chemical synthesis , Triazoles/chemistry , Amyloid beta-Peptides/chemistry , Enkephalin, Leucine/chemistry , Microwaves , Molecular Structure , Oligopeptides/chemical synthesis , Oligopeptides/chemistry , Peptide Fragments/chemistry
9.
Bioorg Med Chem ; 16(8): 4341-6, 2008 Apr 15.
Article in English | MEDLINE | ID: mdl-18329886

ABSTRACT

The opioid receptor system in the central nervous system controls a number of physiological processes, most notably pain. However, most opioids currently available have a variety of side-effects as well as exhibiting tolerance. Tolerance is most likely to be a complex phenomenon, however, the role of receptor internalisation is thought to play a crucial role. In this study, we examined the role of aromaticity in ligand-mediated receptor internalisation of the mu-opioid receptor (MOPR). These studies show that the amount of receptor internalisation may be dependant on the amphiphilicity of the ligand. Specifically, deletion of the C-terminus aromatic residues of endomorphin 1, particularly tryptophan reduces receptor-mediated internalisation whilst the addition of tryptophan within the enkephalin sequence increases receptor internalisation and decreases tolerance.


Subject(s)
Amino Acids, Aromatic/chemistry , Enkephalin, Leucine/chemical synthesis , Enkephalin, Leucine/pharmacology , Oligopeptides/chemical synthesis , Oligopeptides/pharmacology , Receptors, Opioid, mu/antagonists & inhibitors , Cell Line , Chromatography, High Pressure Liquid , Cyclic AMP/biosynthesis , Enkephalin, Leucine/chemistry , Humans , Oligopeptides/chemistry , Receptors, Opioid, mu/metabolism , Spectrometry, Mass, Electrospray Ionization
10.
J Comb Chem ; 9(6): 1012-27, 2007.
Article in English | MEDLINE | ID: mdl-17900168

ABSTRACT

Novel non-PEG derived polyether resins, coined SLURPS (Superior Liquid Uptake Resins for Polymer-supported Synthesis), were studied for their performance in solid-phase synthesis. Novel amino functional resins, SLURPS-NH2, were prepared with a loading of up to 8.5 mmol/g and employed successfully in the solid-phase synthesis of Leu-Enkephalin. The peptide was obtained with the same purity when compared to its synthesis with commercial standard poly(dimethyl acrylamide) resins. Furthermore we show loading and cleavage of aromatic carboxylic acids in excellent yield. The advantageous solvent compatibility of our support was demonstrated through the biphasic dihydroxylation of alkenes with OsO4 in t-BuOH/water mixtures producing bound 1,2-diols and synthesis and removal of a bound oxime using ethanol/water mixtures both in excellent yields. Reactions were easily monitored by gel-phase NMR and FTIR. These results show that SLURPS are very well suited for organic transformations using highly polar solvent mixtures and reagents and at much higher loading levels than standard amphiphilic resins of similar solvent compatibility.


Subject(s)
Enkephalin, Leucine/chemical synthesis , Ethers/chemistry , Neurotransmitter Agents/chemical synthesis , Polyethylene Glycols/chemistry , Resins, Synthetic/chemical synthesis , Alkenes/chemistry , Hydroxylation , Magnetic Resonance Spectroscopy , Models, Chemical , Osmium Tetroxide/chemistry , Oximes/chemistry , Polymethyl Methacrylate/chemistry , Solvents/chemistry
11.
J Pept Sci ; 13(7): 493-7, 2007 Jul.
Article in English | MEDLINE | ID: mdl-17554805

ABSTRACT

Solid-phase peptide synthesis has many advantages compared with solution peptide synthesis. However, this procedure requires a large amount of organic solvents. Since safe organic solvent waste disposal is an important environmental problem, a technology based on coupling reaction of suspended nanoparticle reactants in water was studied. Fmoc-amino acids are used widely, but most of them show low solubility in water. We prepared well-dispersible Fmoc-amino acid nanoparticles in water by pulverization using a planetary ball mill in the presence of poly(ethylene glycol). Leu-enkephalin amide was prepared successfully using the nanoparticulate Fmoc-amino acid on a poly(ethylene glycol)-grafted Rink amide resin in water.


Subject(s)
Amino Acids/chemistry , Nanoparticles/chemistry , Peptides/chemical synthesis , Water/chemistry , Amides/chemical synthesis , Amides/chemistry , Chromatography, High Pressure Liquid , Enkephalin, Leucine/chemical synthesis , Enkephalin, Leucine/chemistry , Microscopy, Electron, Scanning , Nanoparticles/ultrastructure , Peptides/chemistry
12.
Glycoconj J ; 22(3): 83-93, 2005 Mar.
Article in English | MEDLINE | ID: mdl-16133829

ABSTRACT

Emulating the basic principles followed by nature to build its vast repertoire of biomolecules, organic chemists are developing many novel multifunctional building blocks and using them to create 'nature-like' and yet unnatural organic molecules. Sugar amino acids constitute an important class of such polyfunctional scaffolds where the carboxyl, amino and hydroxyl termini provide an excellent opportunity to organic chemists to create structural diversities akin to Nature's molecular arsenal. This article describes some of our works on various sugar amino acids and many other related building blocks, like furan amino acids, pyrrole amino acids etc. used in wide-ranging peptidomimetic studies.


Subject(s)
Amino Acids/chemistry , Drug Design , Furans/chemical synthesis , Sugar Acids/chemistry , Amino Acids/chemical synthesis , Carbohydrate Sequence , Combinatorial Chemistry Techniques , Enkephalin, Leucine/chemical synthesis , Enkephalin, Leucine/chemistry , Furans/chemistry , Models, Molecular , Molecular Conformation , Molecular Mimicry , Peptides, Cyclic/chemical synthesis , Peptides, Cyclic/chemistry , Peptoids/chemistry , Pyrroles/chemical synthesis , Pyrroles/chemistry , Sugar Acids/chemical synthesis
13.
J Org Chem ; 70(8): 3251-5, 2005 Apr 15.
Article in English | MEDLINE | ID: mdl-15822988

ABSTRACT

A new strategy for the synthesis of oligopeptides was developed using an ionic liquid as a soluble support. The efficiency of this ionic liquid-phase approach was demonstrated by the synthesis of a bioactive pentapeptide, Leu(5)-enkephalin, in good yield and reasonable purity. The structures and purities of the reaction intermediates in each step were verified easily by routine spectroscopic analysis, and no chromatographic procedures were needed during the synthesis.


Subject(s)
Enkephalin, Leucine/chemical synthesis , Oligopeptides/chemical synthesis , Amino Acid Sequence , Magnetic Resonance Spectroscopy , Molecular Structure
14.
Biopolymers ; 80(2-3): 151-63, 2005.
Article in English | MEDLINE | ID: mdl-15660379

ABSTRACT

Parallel synthesis of peptides and peptidomimetics has been an important approach to search for biologically active ligands. A novel systematic synthesis of different size bicyclic dipeptide mimetics was developed on solid-phase supports. By taking advantage of the enantioselective synthesis of omega-unsaturated amino acids and their N-methylated derivatives, the hemiaminal problem was prevented in the pathway to thiazolidine formation. The bicyclic dipeptide was generated on the solid-phase support in three steps by an unconventional method. By inserting this bicyclic scaffold into the synthesis of a larger bioactive peptide, 11 different sizes of bicyclo[2,3]-Leu-enkephalin analogues were synthesized in a fast and efficient way. Modeling studies show that a reversed turn structure at positions 2-3 was favored when an L- and L-bicyclic scaffold was used, and that an extended conformation at the N-terminal was favored when a D- and L-bicyclic scaffold was inserted. Binding affinities and bioassay studies show ligands with micromolar binding affinities and antagonist bioactivities for the [6,5]- and [7,5]-bicyclo-Leu-enkephalin analogues.


Subject(s)
Enkephalin, Leucine/analogs & derivatives , Enkephalin, Leucine/chemical synthesis , Enkephalin, Leucine/chemistry , Enkephalin, Leucine/pharmacology , Models, Molecular , Molecular Mimicry , Molecular Structure , Narcotic Antagonists , Protein Conformation
15.
Org Lett ; 6(19): 3285-8, 2004 Sep 16.
Article in English | MEDLINE | ID: mdl-15355033

ABSTRACT

[structure: see text] External bicyclic beta-turn dipeptide mimetics provide an excellent design approach that can offer a rich chiral ensemble of structures with different backbone conformations. We report herein a novel design of a convergent combinatorial synthetic methodology, which is illustrated by the solid-phase synthesis of a series of [3.3.0]-bicyclo([2,3])-Leu-enkephalin analogues. The reactions were optimized and the epimeric configurations were determined by 2D NMR spectroscopy. Biological assays show that these analogues have more potent delta binding affinity and bioactivity for delta vs micro opioid receptor, which may be related to the different conformations preferred by these analogues in our modeling studies.


Subject(s)
Dipeptides/chemical synthesis , Drug Design , Enkephalin, Leucine/analogs & derivatives , Enkephalin, Leucine/chemical synthesis , Protein Structure, Secondary , Dipeptides/pharmacology , Enkephalin, Leucine/pharmacology , Models, Molecular , Molecular Mimicry , Molecular Structure , Receptors, Opioid, delta/metabolism , Receptors, Opioid, mu/metabolism , Stereoisomerism
16.
J Org Chem ; 69(10): 3500-8, 2004 May 14.
Article in English | MEDLINE | ID: mdl-15132562

ABSTRACT

A beta-turn mimetic in which the four amino acids of a beta-turn have been replaced by a 10-membered ring has been designed, synthesized, and subjected to conformational studies. In the mimetic, the intramolecular CO(i)-HN(i)(+3) hydrogen bond that is often found in beta-turns has been replaced by an ethylene bridge. In addition, the amide bond between residues i and i + 1 was exchanged for a methylene ether isoster. Such a beta-turn mimetic, based on the first four residues of Leu-enkephalin (Tyr-Gly-Gly-Phe-Leu), was prepared in 15 steps. The synthesis relied on a beta-azido alcohol prepared in five steps from Cbz-Tyr(tBu)-OH as a key, i-position building block. tert-Butyl bromoacetate, glycine, and a Phe-Leu dipetide were then used as building blocks for positions i + 1, i + 2, and i + 3, respectively. Conformational studies based on (1)H NMR data showed that the beta-turn mimetic was flexible, but that it resembled a type-II beta-turn at low temperature. This low energy conformer closely resembled the structure determined for crystalline Leu-enkephalin.


Subject(s)
Enkephalin, Leucine/chemical synthesis , Amino Acids/chemistry , Enkephalin, Leucine/chemistry , Hydrogen Bonding , Magnetic Resonance Spectroscopy , Molecular Mimicry , Molecular Structure , Protein Conformation , Protein Structure, Secondary
17.
Chem Pharm Bull (Tokyo) ; 52(4): 422-7, 2004 Apr.
Article in English | MEDLINE | ID: mdl-15056956

ABSTRACT

A new N-protecting group, ethanesulfonylethoxycarbonyl (Esc), was designed to perform peptide synthesis in both aqueous and organic solvents. Esc-amino acids were prepared by the reaction of Esc-Cl and amino acids. Although Esc-Cl was a highly reactive reagent, it was not stable and decomposed during the purification procedure. A more stable reagent, ethanesulfonylethyl-4-nitrophenyl carbonate (Esc-ONp), was designed for preparation of Esc-amino acids. Esc-ONp was a stable reagent and could be purified by silica gel column chromatography or recrystallization. Esc-amino acids were prepared by the reaction of Esc-ONp and amino acids in good yield. To evaluate Esc-amino acids, Leu-enkephalin amide was synthesized using Esc-amino acids by the solid phase method in water. Removal of the Esc group was performed with 0.025 mol/l NaOH in 50% aqueous ethanol. Leu-enkephalin amide was successfully synthesized on a poly(ethylene glycol)-grafted polystyrene resin. Esc-amino acids have moderate solubility in organic solvents (such as dimethylformamide and acetonitrile). Leu-enkephalin amide was synthesized using Esc-amino acids by the solid phase method in dimethylformamide. Removal of the Esc group was performed with 0.05 mol/l tetrabutylammonium fluoride in dimethylformamide. Synthesis of Leu-enkephalin amide using Esc-amino acids in dimethylformamide was also successful. The yields of synthesis of Leu-enkephalin amide in water and dimethylformamide were 71% and 67%, respectively.


Subject(s)
Amino Acids/chemistry , Amino Acids/chemical synthesis , Peptides/chemical synthesis , Chromatography, High Pressure Liquid , Enkephalin, Leucine/chemical synthesis , Indicators and Reagents , Solubility , Water
18.
Biopolymers ; 71(5): 552-7, 2003.
Article in English | MEDLINE | ID: mdl-14635095

ABSTRACT

As part of an effort to develop peptide-based affinity labels for opioid receptors, [Leu(5)]enkephalin (LeuEnk) and DTLET (Tyr-D-Thr-Gly-Phe-Leu-Thr), potent agonists for delta receptors, were selected as the parent peptides for further modification. The affinity label derivatives were prepared using standard Fmoc solid-phase peptide synthesis in conjunction with Fmoc-Phe(p-NHAlloc) (Fmoc: 9-flourenylmethoxycarbonyl;) and selective modification of the p-amino group on this residue. The electrophilic isothiocyanate and bromoacetamide groups were introduced into the para position of Phe(4); the corresponding free amine-containing peptides were also prepared for comparison. The pure peptides were evaluated in radioligand binding assays using Chinese hamster ovary (CHO) cells expressing delta and micro opioid receptors. Modification of Phe(4) in LeuEnk and DTLET significantly decreased delta-receptor binding affinity (40 to >2,000-fold). Among the synthesized analogues, [Phe(p-NH(2))(4)]DTLET showed the highest delta-receptor binding affinity (IC(50) = 39 nM) and enhanced selectivity for delta receptors compared to DTLET while other derivatives exhibited much lower delta receptor affinity. The differences in affinities between the two series of analogues and between the derivatives of LeuEnk and N,N-dibenzyl[Leu(5)]Enk reported previously suggest subtle differences in interactions of Phe(4) with delta receptors depending on other modifications in the sequences.


Subject(s)
Affinity Labels , Enkephalin, Leucine/analogs & derivatives , Receptors, Opioid, delta , Staining and Labeling , Animals , CHO Cells , Cricetinae , Enkephalin, Leucine/chemical synthesis , Radioligand Assay , Receptors, Opioid, delta/chemistry , Receptors, Opioid, mu
19.
Chem Commun (Camb) ; (13): 1598-9, 2003 Jul 07.
Article in English | MEDLINE | ID: mdl-12868772

ABSTRACT

Novel constrained beta-turn dipeptide mimetics, 8-phenyl thiaindolizidinone amino acids 3, have been synthesized stereoselectively and incorporated into Leu-enkephalin peptides as a replacement of dipeptide Gly3-Phe4 to afford four individual isomers of Leu-enkephalin analogues 6.


Subject(s)
Amino Acid Substitution , Enkephalin, Leucine/analogs & derivatives , Enkephalin, Leucine/chemical synthesis , Molecular Mimicry , Dipeptides/chemical synthesis , Protein Structure, Secondary , Stereoisomerism
20.
Bioorg Med Chem Lett ; 12(21): 3175-8, 2002 Nov 04.
Article in English | MEDLINE | ID: mdl-12372527

ABSTRACT

Modulation of opioid activity was accomplished for analogues of Leu-enkephalin through incorporation of a 4-imidazolidinone moiety. The peptide backbone was constrained via a methylene bridge between two neighboring amides within its regular peptide sequence, which was expected to disrupt the secondary structure of the original molecule. Five positional analogues of Leu-enkephalin based on the same sequence and different location of the imidazolidinone-constrict were designed, synthesized, and examined for their affinity to micro-, delta- and kappa-opioid receptors.


Subject(s)
Analgesics, Opioid/chemical synthesis , Analgesics, Opioid/pharmacology , Enkephalin, Leucine/analogs & derivatives , Enkephalin, Leucine/pharmacology , Imidazoles/chemical synthesis , Imidazoles/pharmacology , Chromatography, High Pressure Liquid , Drug Design , Enkephalin, Leucine/chemical synthesis , Indicators and Reagents , Magnetic Resonance Spectroscopy , Methylation , Receptors, Opioid, delta/drug effects , Receptors, Opioid, kappa/drug effects , Receptors, Opioid, mu/drug effects , Structure-Activity Relationship
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