Synthesis and activity of 2-oxoamides containing long chain beta-amino acids.

2-Oxoamides based on long chain beta-amino acids were synthesized. 1-Benzyl substituted long chain amines, needed for such synthesis, were synthesized starting from Boc-phenylalaninol. The oxidative conversion of a phenyl group to a carboxyl group was used as the key transformation synthetic step. The compounds synthesized were studied for their activity against GIVA PLA(2), and were proven to be weak inhibitors.     

Synthesis of tetrazole analogs of gamma- and delta-amino acids.

N-benzyloxycarbonyl-protected alpha- or beta-amino alcohols, easily prepared from alpha- and beta-amino acids, were converted into aldehydes and directly reacted with (triphenyl phosphoranylidene) acetonitrile, leading to unsaturated nitriles. Treatment of nitriles with NaN(3) and ZnBr(2) produced unsaturated gamma- and delta-amino tetrazoles, which were deprotected and converted to the corresponding saturated compounds by catalytic hydrogenation. For the case of delta-amino tetrazole, the methylation of the acidic moiety occurred after treatment with CH(2)N(2), leading to the N(1)- and N(2)-methylated constitutional isomers, which were separated by column chromatography and hydrogenated.     

Crystal-state conformation of Calpha,alpha-dialkylated peptides containing chiral beta-homo-residues.

Secondary structure formation and stability are essential features in the knowledge of complex folding topology of biomolecules. To better understand the relationships between preferred conformations and functional properties of beta-homo-amino acids, the synthesis and conformational characterization by X-ray diffraction analysis of peptides containing conformationally constrained Calpha,alpha-dialkylated amino acid residues, such as alpha-aminoisobutyric acid or 1-aminocyclohexane-1-carboxylic acid and a single beta-homoamino acid, differently displaced along the peptide sequence have been carried out. The peptides investigated are: Boc-betaHLeu-(Ac6c)2-OMe, Boc-Ac6c-betaHLeu-(Ac6c)2-OMe and Boc-betaHVal-(Aib)5-OtBu, together with the C-protected beta-homo-residue HCl.H-betaHVal-OMe. The results indicate that the insertion of a betaH-residue at position 1 or 2 of peptides containing strong helix-inducing, bulky Calpha,alpha-disubstituted amino acid residues does not induce any specific conformational preferences. In the crystal state, most of the NH groups of beta-homo residues of tri- and tetrapeptides are not involved in intramolecular hydrogen bonds, thus failing to achieve helical structures similar to those of peptides exclusively constituted of Calpha,alpha-disubstituted amino acid residues. However, by repeating the structural motifs observed in the molecules investigated, a beta-pleated sheet secondary structure, and a new helical structure, named (14/15)-helix, were generated, corresponding to calculated minimum-energy conformations. Our findings, as well as literature data, strongly indicate that conformations of betaH-residues, with the micro torsion angle equal to -60 degrees, are very unlikely.     

Synthesis and conformational studies of pseudopeptides containing an unsymmetrical triazine scaffold.

Solid-phase synthesis and conformational studies of two pseudopeptides constituted by a triazine scaffold bound to two peptidic arms are described. In this paper, a new scaffold based on unsymmetrical triamino 1,3,5-triazine bearing two alkyl chains has been designed, assisted by molecular modelling, as a mimic of the backbone of the i + 1 and i + 2 residues of a beta-turn. The results confirm the ability of the triazine scaffold to induce extended conformations of the peptidic strands and point out that this scaffold is a good candidate as a template to induce anti-parallel beta-sheet structure.     

A bioactive somatostatin analog without a type II' beta-turn: synthesis and conformational analysis in solution.

A cyclic somatostatin analog [structure: see text] (1) has been synthesized. Biological assays show that this compound has strong binding affinities to somatostatin hsst2 and hsst5 receptor subtypes (5.2 and 1.2 nM, respectively, and modest affinity to hsst4 (41.1 nM)). Our conformational analysis carried out in DMSO-d6 indicates that this compound exists as two structures arising from the trans and cis configurations of the peptide bond between Phe7 and N-alkylated Gly8. However, neither conformer exhibits a type II' beta-turn. This is the first report of a potent bioactive somatostatin analog that does not exhibit a type II' beta-turn in solution. Molecular dynamics simulations (500 ps) carried out at 300 K indicate that the backbone of compound 1 is more flexible than other cyclic somatostatin analogs formed by disulfide bonds.     

The role of pi-acidic and pi-basic chiral stationary phases in the high-performance liquid chromatographic enantioseparation of unusual beta-amino acids

The application of 3,5-dimethylphenyl-carbamoylated-beta-cyclodextrin (Cyclobond I 2000 DMP) and 2,6-dinitro-4-trifluoromethylphenyl-ether-beta-cyclodextrin-based (Cyclobond DNP) chiral stationary phases for the high-performance liquid chromatographic enantioseparation of unusual beta-amino acids is reported. The investigated amino acids were saturated or unsaturated alicyclic beta-3-homo-amino acids and bicyclic beta-amino acids. Prior to chromatographic analyses, all amino acids were transformed to N-3,5-dinitrobenzoyl- or N-3,5-dimethylbenzoyl form to ensure a pi-acidic or pi-basic function and to enhance the pi-acidic-pi-basic interactions between analytes and chiral selectors. Chromatographic results are given as retention, separation and resolution factors. The chromatographic conditions were varied to achieve optimal separation. The sequence of elution of the enantiomers was determined in some cases.     

Hybrid alpha/beta3-peptides with proteinogenic side chains. Monosubstituted analogues of the chemotactic tripeptide For-Met-Leu-Phe-OMe.

The alpha/beta3-mixed tripeptides R-CO-beta3-HMet-Leu-Phe-OMe (1a,b), R-CO-Met-beta3-HLeu-Phe-OMe (2a,b) and R-CO-Met-Leu-beta3-HPhe-OMe (3a,b) (a, R = tert-butyloxy-; b, R = H-), analogues of the potent chemoattractant For-Met-Leu-Phe-OMe, have been synthesized by classical solution methods and fully characterized. The activities of the new analogues as chemoattractants, superoxide anion producers and lysozyme releasers have been determined on human neutrophils. Whereas all of the three N-formyl derivatives are significantly less active than the parent tripeptide as chemoattractants, compound 1b has been found to be highly active as a superoxide anion producer and 3b as a lysozyme releaser. The results show that the replacement of the native Leu residue at the central position is, in each of the examined cases, the least favourable modification. The three N-Boc derivatives are, as expected, devoid of activity as agonists, but they are all good inhibitors of chemotaxis. Information on the solution conformation has been obtained by examining the involvement of the NH groups in intramolecular H-bonds using 1H NMR. The conformation of the N-Boc analogue 1a has also been determined in the crystal state by x-ray diffraction analysis. The molecule is extended at the beta3-HMet residue (phi1 = -87 degrees; theta1 = 172 degrees; psi1 = 126 degrees) and no intramolecular H-bond is present.     

Synthesis and secondary structure of oligo(alpha-isobutyl beta,L-aspartate)s

The oligo(beta-peptide)s, hexa(alpha-isobutyl beta,L-aspartate) (Hex-AIBLA) and octa(alpha-isobutyl beta,L-aspartate) (Oct-AIBLA), were synthesized in solution by using standard coupling methods. Powder x-ray diffraction showed that the octamer crystallized in the two helical crystal forms known to exist in the homologous poly(beta-peptide), whereas the hexamer seemed to adopt an extended conformation. Both CD and 1H-NMR spectra of Oct-AIBLA in MeOH revealed the presence of a regularly folded conformation in this solvent, presumably the 3(14) helix. The helix-to-coil transition of Oct-AIBLA was observed to take place upon heating in both MeOH and CHCl3, in the second case associated with a not-well-defined aggregation-disaggregation process. The spectroscopic evidence obtained on the presence of folded structures in Hex-AIBLA were much weaker than for the octamer.     

Peptides containing 4-amino-1,2-dithiolane-4-carboxylic acid (Adt): conformation of Boc-Adt-Adt-NHMe and NH...S interactions.

To study the conformational preferences induced by the insertion of the 4-amino-1,2-dithiolane-4-carboxylic acid (Adt) residue into a peptide backbone, the achiral N-protected dipeptide methylamide Boc-Adt-Adt-NHMe (1) was synthesized and its crystal state and solution conformation studied and compared with that exhibited by its carba-analogue Boc-Ac5c-Ac5c-NHMe containing two residues of 1-aminocyclopentane-1-carboxylic acid (Ac5c). Compound 1 in the crystal adopts a type-III beta-turn conformation and an analogous structure is that preferred in chloroform solution as established by 1H-NMR and NOE information. In the crystal packing three different Adt rings form a cavity and the involved sulphur atoms give rise to unusual multiple interactions with one NH group. The chemical nature of these intermolecular and intramolecular main-chain...side-chain NH...S interactions are discussed in terms of quantum chemical calculations.     

Crystal-state 3D-structural characterization of novel 3(10)-helical peptides.

The crystal-state conformations of two octapeptides, pBrBz-(D-Iva)8-OtBu (8I) and Ac-[L-(alphaMe)Val]8-OH (8II), the heptapeptide Z-[L-(alphaMe)Val]7-OH (7), the hexapeptide Z-[L-(alphaMe)Leu]6-OtBu (6) and the tetrapeptide alkylamide Z-(Aib)2-L-Glu(OMe)-L-Ala-L-Lol (5) were assessed by x-ray diffraction analyses. Two independent molecules are observed in the asymmetric unit of each L-(alphaMe)Val homo-peptide. All four homo-peptides are folded in a regular 3(10)-helical structure (only the C-terminal H-bonded conformation of the D-Iva octapeptide is distorted to a type-I beta-turn). The hydroxyl groups of the C-terminal carboxyl moieties of the two L-(alphaMe)Val homo-peptides participate in an oxy-analogue of the type-III beta-turn conformation. While the two L-(alphaMe)Val 3(10)-helices are right-handed, the D-Iva and L-(alphaMe)Leu helices are left-handed. The tetrapeptide alkylamide is 3(10)-helical at the N-terminus, but it is mixed 3(10)/alpha-helical at the C-terminus.     

Conformational investigation of alpha,beta-dehydropeptides. XVI. Beta-turn tendency in Ac-Pro-DeltaXaa-NHMe: crystallographic and theoretical studies.

The crystal structures of two diastereomeric alpha,beta-dehydrobutyrine peptides Ac-Pro-(Z)-DeltaAbu-NHMe (I) and Ac-Pro-(E)-DeltaAbu-NHMe (II) have been determined. Both dehydropeptides adopt betaI-turn conformation characterized by the pairs of (phi(i+1), psi(i+1)) and (phi(i+2), psi(i+2)) angles as -66, -19, -97, 11 degrees for I and -59, -27, -119, 29 degrees for II. In each peptide, the betaI turn is stabilized by (i + 3) --> i intramolecular hydrogen bonds with N...O distance of 3.12 A for I and 2.93 A for II. These structures have been compared to the crystal structures of homologous peptides Ac-Pro-DeltaVal-NHMe and Ac-Pro-DeltaAla-NHMe. Theoretical analyses by DFT/B3LYP/6-31 + G** method of conformers formed by these four peptides and by the saturated peptide Ac-Pro-Ala-NHMe revealed that peptides with a (Z) substituent at the C(beta) (i+2) atom of dehydroamino acid, i.e. Ac-Pro-DeltaVal-NHMe and Ac-Pro-(Z)-DeltaAbu-NHMe, predominantly form beta turns, both in vacuo and in polar environment. The tendency to adopt beta-turn conformation is much weaker for the peptides lacking the (Z) substituent, Ac-Pro-(E)-DeltaAbu-NHMe and Ac-Pro-DeltaAla-NHMe. The latter adopts a semi-extended or an extended conformation in every polar environment, including a weakly polar solvent. The saturated peptide Ac-Pro-Ala-NHMe in vacuo prefers a beta-turn conformation, but in polar environment the differences between various conformers are small. The role of pi-electron correlation and intramolecular hydrogen bonds interaction in stabilizing the hairpin structures are discussed.     

Rigid nonproteinogenic cyclic amino acids as ligands for glutamate receptors: trans-tris(homoglutamic) acids

The second-generation asymmetric synthesis of the trans-tris(homoglutamic) acids reported herein proceeds via Strecker reaction of chiral ketimines, obtained from condensation of racemic 2-ethoxycarbonylmethylcyclopentanone and commercially available (S)- and (R)-1-phenylethylamine, respectively. In the key stereodifferentiating step, the cyanide addition leads to mixtures of diastereomeric alpha-amino nitrile-esters, the composition of which is independent of the reaction temperature and the type of the solvent, respectively. Hydrolysis of the alpha-amino nitrile-esters with concentrated H(2)SO(4) yielded diastereomeric mixtures of secondary alpha-amino amido-esters, which after separation were hydrogenolyzed and hydrolyzed each to the enantiomeric trans-1-amino-2-carboxymethylcyclopentanecarboxylic acids. Their configuration was completely established by NMR methods, CD spectra, and X-ray analysis of the trans-1S,2R-configured secondary alpha-amino amido-ester. In receptor binding assays and functional tests, trans-1S,2R-1-amino-2-carboxymethylcyclopentanecarboxylic acid hydrochloride was found to behave as a selective mGluR(2)-antagonist without relevant binding properties at iGluRs.     

Studies on intramolecular hydrogen bonding between the pyridine nitrogen and the amide hydrogen of the peptide: synthesis and conformational analysis of tripeptides containing novel amino acids with a pyridine ring.

For the first time tripeptides, Z-AA(1)-Xaa-AA(3)-OMe (AA(1) and AA(3) = Gly or Aib, Xaa = 2Pmg and 2Pyg) were prepared containing alpha-methyl-alpha-(2-pyridyl)glycine (2Pmg) and alpha-(2-pyridyl)glycine (2Pyg) by solid-phase Ugi reaction. These results clearly indicate that for the preparation of tripeptides containing an amino acid with a pyridine ring, the solid-phase Ugi reaction is very useful.NMR analysis clarified that 2Pmg-containing tripeptides adopt a unique conformation with an intramolecular hydrogen bond between 2Pmg-NH and the pyridine nitrogen. However, in the case of Z-Gly-2Pyg-Gly-OMe, the intramolecular hydrogen bonding between 2Pyg-NH and the pyridine nitrogen was not observed, whereas Z-Aib-2Pyg-Aib-OMe adopts a unique conformation with an intramolecular hydrogen bond between 2Pyg-NH and a pyridine nitrogen. Conformational analysis of the tripeptides, Z-AA(1)-Xaa-AA(3)-OMe (AA(1), AA(3) = Gly or Aib, Xaa = alpha,alpha-di(2-pyridyl)glycine (2Dpy), alpha-phenyl-alpha-(2-pyridyl)glycine (2Ppg), 2Pmg and 2Pyg), clarified that when an alpha,alpha-disubstituted glycine with a 2-pyridyl group at an alpha-carbon atom is introduced into any peptide, an intramolecular hydrogen bond between a pyridine nitrogen and an amide proton is formed and conformational mobility of the peptide backbone is restricted.     

Conformational investigation of alpha, beta-dehydropeptides. XI. Molecular and crystal structure of Ac-(Z)-deltaPhe-NMe2 as compared to those of related molecules.

A series of three homologous dimethyldiamides Ac-(Z)-deltaPhe-NMe2, Ac-L-Phe-NMe2 and Ac-DL-Phe-NMe2 have been synthesized and their structures determined from single-crystal X-ray diffraction data. To learn more about the conformational preferences of the compounds studied, the fully relaxed phi, psi conformational energy maps on the free molecules of Ac-deltaAla-NMe2 and Ac-(Z)-deltaPhe-NMe2 were obtained with the HF/3-21G method and the calculated minima re-optimized with the DFT/B3LYP/6-31G** method. The crystal state results have been compared with the literature data. The studied dimethyldiamide Ac-deltaXaa-NMe2 combines the double bond in positions alpha, beta and the C-terminal tertiary amide within one molecule. As the representative probe with deltaXaa = deltaAla, (Z)-deltaLeu and (Z)-deltaPhe shows, in the solid state they adopt the conservative conformation with phi, psi approximately -45 degrees, approximately 130 degrees and with a non-planar tertiary amide bond, whatever the packing forces are. This conformation is located on the Ramachandran map in region H/F, which is of high-energy for common amino acids, but not so readily accessible to them. The free molecule calculations on Ac-deltaAla-NMe2 and Ac-(Z)-deltaPhe-NMe2 reveal that, in spite of dissimilar overall conformational profiles of these molecules, this structure is one of their low-energy conformers and for Ac-(Z)-deltaPhe-NMe2 it constitutes the global minimum. So, the theoretical results corroborate those experimental results proving that this structure is robust enough to avoid conformational distortion due to packing forces. In contrast to Ac-deltaXaa-NMe2, the saturated Ac-L/DL-Xaa-NMe2 shows the constancy of the associative patterns but do not prefer any molecular structure in the solid state.     

Conformational investigation of alpha,beta-dehydropeptides. XV: N-acetyl-alpha,beta-dehydroamino acid N 'N '-dimethylamides: conformational properties from infrared and theoretical studies.

The FTIR spectra were analysed in the region of the nu(s)(N-H), AI(C=O) and nu(s)(Calpha=Cbeta) bands for a series of Ac-DeltaXaa-NMe2, where DeltaXaa = DeltaAla, (Z)-DeltaAbu, (Z)-DeltaLeu, (Z)-DeltaPhe and DeltaVal, to determine a predominant solution conformation of these alpha,beta-dehydropeptide-related molecules. Measurements were taken in CCl4, DCM and MeCN solutions. In the same way, spectra of saturated analogues Ac-Xaa-NMe2, where Xaa = Ala, Abu, Leu, Phe and Val, were investigated. To help interpret the spectroscopic results, conformational maps were calculated by the B3LYP/6-31+G** method. Also, the relative energies of all conformers of the dehydro compounds in vacuo as well as in the studied solvents in addition to the theoretical IR frequencies of these conformers were calculated. For comparison, molecules of two saturated analogues, Ac-L-Ala-NMe2 and Ac-L-Phe-NMe2, were calculated in a similar way. Both unsaturated and saturated compounds, which have an aliphatic side chain, occur in CCl4 and DCM mainly as a mixture of extended conformers with the C5 H-bond and open conformers. As solvent polarity increases, participation of the open conformers also increases, and in MeCN, the model amides are almost exclusively in the open form, except Ac-DeltaAla-NMe2, which shows a small amount of the H-bonded conformer. Ac-DeltaAla-NMe2 and Ac-DeltaAbu-NMe2 have stronger C5 hydrogen bonds than those of their saturated counterparts. As the calculations indicate, the open conformation of the unsaturated amides is conformer H/F with phi, psi -44 +/- 5 degrees, 127 +/- 4 degrees. This is the second lowest in energy conformer in vacuo and in CCl4 and the lowest one in more polar solvents. The open conformation of Ac-L-Ala-NMe2 constitutes conformer C with phi, psi -101.5 degrees, 112.7 degrees. For Ac-DeltaAla-NMe2 and Ac-DeltaAbu-NMe2, FTIR also reveals the presence of a third conformer. Calculations indicate that is the semiextended conformer D with the N1-H1...N2 hydrogen bond/contact. In all solvents, Ac-L-Phe-NMe2 and Ac-(Z)-DeltaPhe-NMe2 show only the extended E and the open H/F, respectively. In both there is an amide/pi(Ph) interaction.     

Synthesis and biological activity profile of new analogues of the cyclic opioid peptide H-Tyr-c[D-Cys-Gly-Phe(pNO2)-D-Cys]-NH2 containing (S)-alpha-hydroxymethylcysteine in place of cysteine.

To examine the effect on biological activity of replacing D-Cys in the opioid peptide H-Tyr-c[D-Cys-Gly-Phe(pNO(2))-D-Cys]-NH(2) in position 2 or/and 5 with alpha-hydroxymethylcysteine (alpha-Hmc), three analogues were synthesized. These compounds exhibit agonist activity at both mu and delta receptors. However, the most active analogue, with (S)-alpha-Hmc residue in position 5, was 3360- and 2190-fold less active than the parent peptide in the GPI and MVD assays, respectively.     

Folding of peptides characterized by c3Val,a highly constrained analogue of valine

Using a combined chemical/chiral chromatographic approach we synthesized an N-protected derivative of (R)-c(3)Val, a severely conformationally restricted C(alpha)-tetrasubstituted alpha-amino acid characterized by a C(beta,beta)-dimethylated cyclopropane system. A set of terminally protected derivatives and model peptides (to the heptamer level), containing one or two (R)-c(3)Val residues in combination with either Aib or Gly residues, was prepared by solution methods. A detailed solution and crystal-state conformational investigation, based on Fourier transform infrared (FTIR) absorption, (1)H-NMR, and x-ray diffraction techniques, performed in comparison with a similar study on related derivatives and peptides rich in (alphaMe)Val, the prototype of C(alpha)-tetrasubstituted alpha-amino acids of this subfamily, allowed us to conclude the following: (a) c(3)Val is a good beta-bend and helix former, although less efficient than (alphaMe)Val. (b) The relationship between alpha-carbon chirality and screw sense of the folded structure formed is the same as that of (alphaMe)Val, i.e., the (R)-enantiomer has a strong left-handed bias. (c) c(3)Val seems more prone than (alphaMe)Val to fold into a gamma-bend conformation. The conformational propensities of C(beta,beta)-disubstituted Ac(3)c residues are also discussed in comparison with those of the parent cyclopropane residue.     

Conformational investigation of alpha,beta-dehydropeptides. N-acetyl-(E)-dehydrophenylalanine N'-methylamide: conformational properties from infrared and theoretical studies, part XIV.

N-Acetyl-(E)-dehydrophenylalanine N'-methylamide [Ac-(E)-DeltaPhe-NHMe], one of a few representative (E)-alpha,beta-dehydroamino acids, was studied by FTIR in dichloromethane and acetonitrile. To support spectroscopic interpretations and to gain some deeper insight into the Ac-(E)-DeltaPhe-NHMe molecule, the Ramachandran potential energy surface was calculated by the B3LYP/6-31G*//HF/3-21G method and the conformers localized were fully optimized at the B3LYP/6-31 + G** level. The spectra and calculations were compared with those of the related molecules Ac-DeltaAla-NHMe and Ac-(Z)-DeltaPhe-NHMe. The title compound assumes two conformational states in equilibrium in dichloromethane solution with a predominance of the extended conformer E. The Ac-(E)-DeltaPhe-NHMe spectrum is like that of Ac-DeltaAla-NHMe, particularly in the region of bands AI and AII, and unlike that of Ac-(Z)-DeltaPhe-NHMe. The positions of bands AI and II together with the nu(s)(N1--H1) band proves that the conformers E of both DeltaAla and (E)-DeltaPhe compounds are stabilized by the quite strong C5 hydrogen bonds N1--H1...O2. The same conclusion is drawn from the Ramachandran diagrams. The conformers E of both compounds are placed in the global minima and the gaps in energy order between them and the second conformer are large. The conformers E of DeltaAla and (E)-DeltaPhe, apart from the N1--H1...O2 hydrogen bond, show the Cbeta--H...O1 interaction, and Ac-(E)-DeltaPhe-NHMe displays the NH/pi interaction with the N2--H2 projecting in the first carbon atom of the phenyl ring. The C5 hydrogen bond is stronger in (E)-DeltaPhe than that in the DeltaAla compound. This is in agreement with interactions found in the calculated structures and can be explained by the influence of the phenyl ring in position (E). In acetonitrile, the molecule of Ac-(E)-DeltaPhe-NHMe loses its C5 hydrogen bond and becomes unfolded, whereas that of Ac-DeltaAla-NHMe does not vary practically. Adopting conformation E in a non-polar solvent seems to be a general feature of the (E)-DeltaXaa residues.     

Heterochiral Ala/(αMe)Aze sequential oligopeptides: Synthesis and conformational study

α‐Amino acid residues with a ?,ψ constrained conformation are known to significantly bias the peptide backbone 3D structure. An intriguing member of this class of compounds is (αMe)Aze, characterized by an N^α‐alkylated four‐membered ring and C^α‐methylation. We have already reported that (S)‐(αMe)Aze, when followed by (S)‐Ala in the homochiral dipeptide sequential motif ‐(S)‐(αMe)Aze‐(S)‐Ala‐, tends to generate the unprecedented γ‐bend ribbon conformation, as formation of a regular, fully intramolecularly H‐bonded γ‐helix is precluded, due to the occurrence of a tertiary amide bond every two residues. In this work, we have expanded this study to the preparation and 3D structural analysis of the heterochiral (S)‐Ala/(R)‐(αMe)Aze sequential peptides from dimer to hexamer. Our conformational results show that members of this series may fold in type‐II β‐turns or in γ‐turns depending on the experimental conditions.     

Synthesis and receptor binding of opioid peptide analogues containing β3‐homo‐amino acids

β‐Amino acids containing hybrid peptides and β‐peptides show great potential as peptidomimetics. In this paper we describe the synthesis and affinity toward the µ‐ and δ‐opioid receptors of β‐peptides, analogues of Leu‐enkephalin, deltorphin I, dermorphin and α,β‐hybrides, analogues of deltorphin I. Substitution of α‐amino acid residues with β³‐homo‐amino acid residues, in general resulted in decrease of affinity to opioid receptors. However, the incorporation β³h‐D ‐Ala in position 2 or β³hPhe in position 3 of deltorphin I resulted in potent and selective ligand for δ‐opioid receptor. The NMR studies of β‐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. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd.